Cyclic hexapeptides having antibiotic activity

ABSTRACT

This invention relates to new polypeptide compound represented by general formula (I), wherein R 1 , R 2 , R 3 , R 4 , R 5  and R 6  are as defined in the description or a salt thereof which has antimicrobial activities (especially, antifungal activities), inhibitory activity on β-1,3-glucan synthase, to process for preparation thereof, to a pharmaceutical composition comprising the same, and to a method for prophylactic and/or therapeutic treatment of infectious diseases including  Pneumocystis carinii  infection (e.g.  Pneumocystis carinii  pneumonia) in a human being or an animal.

This application is a 371 of PCT/JP00/02710, filed Apr. 25, 2000, whichclaims priority to Australian PP 9997, filed Apr. 27, 1999.

TECHNICAL FIELD

The present invention relates to new polypeptide compounds and saltsthereof which are useful as a medicament.

BACKGROUND ART

In U.S. Pat. Nos. 5,376,634, 5,569,646, WO 96/11210 and WO 99/40108,there are disclosed the polypeptide compound and a pharmaceuticallyacceptable salt thereof, which have antimicrobial activities (especiallyantifungal activity).

DISCLOSURE OF INVENTION

The present invention relates to new polypeptide compound and a saltthereof.

More particularly, it relates to new polypeptide compound and a saltthereof, which have antimicrobial activities [especially, antifungalactivities, in which the fungi may include Aspergillus, Cryptococcus,Candida, Mucor, Actinomyces, Histoplasma, Dermatphyte, Malassezia,Fusarium and the like.], inhibitory activity on β-1,3-glucan synthase,and further which are expected to be useful for the prophylactic and/ortherapeutic treatment of Pneumocystis carinii infection (e.g.Pneumocystis carinii pneumonia) in a human being or an animal, to aprocess for preparation thereof, to a pharmaceutical compositioncomprising the same, and to a methods for the prophylactic and/ortherapeutic treatment of infectious disease including Pneumocystiscarinii infection (e.g. Pneumocystis carinii pneumonia) in a human beingor an animal.

The object polypeptide compounds of the present invention are new andcan be represented by the following general formula (I):

wherein

-   -   R¹ is hydrogen or acyl group,    -   R² and R³ are independently hydrogen, lower alkyl which may have        one or more suitable substituent(s), acyl group, heterocyclic        group which may have one or more suitable substituent(s), lower        alkylidenyl which may have one or more suitable substituent(s),        higher alkyl which may have one or more suitable substituent(s)        or cyano,    -   R⁴ is hydrogen or hydroxy,    -   R⁵ is hydrogen, hydroxy, lower alkoxy or hydroxysulfonyloxy, and    -   R⁶ is hydroxy or acyloxy,        or a salt thereof.

The new polypeptide compound (I) or a salt thereof can be prepared bythe process as illustrated in the following reaction schemes.

The Starting compound (II) or a salt thereof can be prepared by theprocess as illustrated in the following reaction scheme.

wherein

-   -   R¹, R², R³, R⁴, R⁵ and R⁶ are defined above,    -   R_(a) ¹ is acyl group,    -   R_(a) ² is hydrogen, lower alkyl which may have one or more        suitable substituent(s), acyl group, heterocyclic group which        may have one or more suitable substituent(s), lower alkylidenyl        which may have one or more suitable substituent(s), higher alkyl        which may have one or more suitable substituent(s) or cyano,    -   R_(b) ² is acyl group,    -   R_(a) ³ is lower alkyl which may have one or more suitable        substituent(s), acyl group, heterocyclic group which may have        one or more suitable substituent(s), lower alkylidenyl which may        have one or more suitable substituent(s), higher alkyl which may        have one or more suitable substituent(s) or cyano,    -   R_(b) ³ is amino protective group,    -   R_(c) ³ is acyl group,    -   R_(a) ⁵ is hydroxysulfonyloxy, and    -   R_(b) ⁵ is hydroxy.

Suitable salt of the new polypeptide compound (I) is a pharmaceuticallyacceptable and conventional non-toxic salt, and may include a salt witha base or an acid addition salt such as a salt with an inorganic base,for example, an alkali metal salt (e.g., sodium salt, potassium salt,etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt,etc.), an ammonium salt;

-   a salt with an organic base, for example, an organic amine salt    (e.g., triethylamine salt, diisopropylethylamine salt, pyridine    salt, picoline salt, ethanolamine salt, triethanolamine salt,    dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt,    4-dimethylaminopyridine salt, etc.);-   an inorganic acid addition salt (e.g., hydrochloride hydrobromide,    sulfate, phosphate, etc.);-   an organic carboxylic sulfonic acid addition salt (e.g., formate,    acetate, trifluoroacetate, maleate, tartrate, fumarate,    methanesulfonate, benzenesulfonate, toluenesulfonate, etc.);-   a salt with a basic or acidic amino acid (e.g., arginine, aspartic    acid, glutamic acid, etc.).

Suitable examples and illustration of the various definitions in theabove and subsequent descriptions of the present specification, whichthe present invention intends to include within the scope thereof, areexplained in detail as follows:

The term “lower” is used to intend a group having 1 to 6 carbon atom(s),unless otherwise provided.

Suitable example of “one or more” may be the number of 1 to 6, in whichthe preferred one may be the number of 1 to 3.

Suitable example of “halogen” may be fluorine, chlorine, bromine, iodineand the like.

Suitable example of “lower alkoxy” may include straight or branched onesuch as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert-butoxy, pentyloxy, tert-pentyloxy, neo-pentyloxy, hexyloxy,isohexyloxy and the like.

Suitable example of “higher alkoxy” may include straight or branched onesuch as heptyloxy, octyloxy, 3,5-dimethyloctyloxy, 3,7-dimethyloctyloxy,nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy,hexadecyloxy, heptadecyloxy, octadecyloxy, nonadecyloxy, icosyloxy, andthe like.

Suitable example of “lower alkyl” may include straight or branched onehaving 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl, neo-pentyl,hexyl, isohexyl and the like.

Suitable example of “higher alkyl” may include straight or branched onesuch as heptyl, octyl, 3,5-dimethyloctyl, 3,7-dimethyloctyl, nonyl,decyl, undecyl, dodecyl, tridecyl, tetradecyl, hexadecyl, heptadecyl,octadecyl, nionadecyl, icosyl, and the like.

Suitable example of “aryl” and “ar” moiety may include phenyl which mayhave lower alkyl (e.g., phenyl, mesityl, xylyl, tolyl, etc.), naphthyl,anthryl, indanyl, fluorenyl, and the like, and this aryl and “ar” moietymay have one or more halogen.

Suitable example of “aroyl” may include benzoyl, toluoyl, naphthoyl,anthrylcarbonyl, and the like.

Suitable example of “heterocyclic” group may include

-   -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 to 4 nitrogen atom(s), for        example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,        dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl        (e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,        2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 1H-tetrazolyl,        2H-tetrazolyl, etc.), etc.;    -   saturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 to 4 nitrogen atom(s), for        example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl,        azetidinyl, etc.;    -   unsaturated condensed heterocyclic group containing 1 to 4        nitrogen atom(s), for example, indolyl, isoindolyl, indolinyl,        indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl,        benzotriazolyl, etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to        3 nitrogen atom(s), for example, oxazolyl, isoxazolyl,        oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,        1,2,5-oxadiazolyl, etc.), etc.;    -   saturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to        3 nitrogen atom(s), for example, morpholinyl, sydnonyl,        morpholino, etc.;    -   unsaturated condensed heterocyclic group containing 1 or 2        oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,        benzoxazolyl, benzoxadiazolyl, etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to        3 nitrogen atom(s), for example, thiazolyl, isothiazolyl,        thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,        1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl,        etc.;    -   saturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to        3 nitrogen atom(s), for example thiazolidinyl, thiomorpholinyl,        thiomorpholino, etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 sulfur atom(s), for        example, thienyl, dihydrodithiinyl, dihydrodithionyl, etc.;    -   unsaturated condensed heterocyclic group containing 1 or 2        sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,        benziothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing an oxygen atom, for example,        furyl etc.;    -   saturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing 1 or 2 oxygen atom(s), for        example, tetrahydrofuran, tetrahydropyran, dioxacyclopentane,        dioxacyclohexane, etc.;    -   unsaturated 3 to 8-membered (more preferably 5 or 6-membered)        heteromonocyclic group containing an oxygen atom and 1 or 2        sulfur atom(s), for example, dihydrooxathiinyl, etc.;    -   unsaturated condensed heterocyclic group containing 1 or 2        sulfur atom(s), for example benzothienyl, benzodithiinyl, etc.;    -   unsaturated condensed heterocyclic group containing an oxygen        atom and 1 or 2 sulfur atom(s), for example, benzoxathiinyl,        etc.; and the like, and this “heterocyclic group” may have one        or more suitable substituent(s) selected from the group        consisting of lower alkyl, oxo, cyclo(lower)alkyl,        hydroxy(lower)alkyl, carboxy(lower)alkanoyl which may have amino        and heterocycliccarbonyl.

Suitable example of “cyclo(lower)alkyl” may include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like, and this“cyclo(lower)alkyl” may have one or more lower alkyl.

Suitable example of “cyclo(lower)alkyloxy” may include cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

Suitable example of “acyl group” may include aliphatic acyl, aromaticacyl, arylaliphatic acyl and heterocyclic-aliphatic acyl derived fromcarboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and thelike.

Suitable example of said “acyl group” may be illustrated as follows.

-   Carboxy; carbamoyl; mono or di(lower)alkylcarbamoyl (e.g.,    methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl,    diethylcarbamoyl, etc.)

Aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl,propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl,decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl,pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl,icosanoyl, etc.);

-   lower or higher alkoxycarbonyl (e.g., methoxycarbonyl,    ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl,    heptyloxycarbonyl, etc.); lower alkenyloxycarbonyl (e.g.,    vinyloxycarbonyl, propenyloxycarbonyl, allyloxycarbonyl,    butenyloxycarbonyl, butedienyloxycarbonyl, pentenyloxycarbonyl,    hexenyloxycarbonyl, etc.);-   lower or higher alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl,    etc.);-   lower or higher alkoxysulfonyl (e.g., methoxysulfonyl,    ethoxysulfonyl, etc.); or the like;

Aromatic acyl such as

-   aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);-   ar(lower)alkanoyl [e.g., phenyl(C₁-C₆)alkanoyl (e.g., phenylacetyl,    phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl,    phenylhexanoyl, etc.), naphthyl(C₁-C₆)alkanoyl (e.g.,    naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];-   ar(lower)alkenoyl [e.g., phenyl(C₃-C₆)alkenoyl (e.g.,    phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl,    phenylpentanoyl, phenylhexenoyl, etc.), naphthyl(C₃-C₆)alkenoyl    (e.g., naphthylpropenoyl, naphthylbutenoyl, etc.), etc.];-   ar(lower)alkoxycarbonyl [e.g., phenyl(C₁-C₆)alkoxycarbonyl (e.g.,    benzyloxycarbonyl, etc.), fluorenyl(C₁-C₆)alkoxycarbonyl (e.g.,    fluorenylmethyloxycarbonyl, etc.), etc.];-   aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.);-   aryloxy(lower)alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl,    etc.);-   arylcarbamoyl (e.g., phenylcarbamoyl, etc.);-   arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.);-   arylglyoxyloyl (e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.);-   arylsulfonyl which may have 1 to 4 lower alkyl (e.g.,    phenylsulfonyl, p-tolylsulfonyl, etc.); or the like;

Heterocyclic acyl such as

-   heterocycliccarbonyl;-   heterocyclic(lower)alkanoyl (e.g., heterocyclicacetyl,    heterocyclicpropanoyl, heterocyclicbutanoyl, heterocyclicpentanoyl,    heterocyclichexanoyl, etc.);-   heterocyclic(lower)alkenoyl (e.g., heterocyclicpropenoyl,    heterocyclicbutenoyl, heterocyclicpentenoyl, heterocyclichexenoyl,    etc.);-   heterocyclicglyoxyloyl; or the like;-   in which suitable “heterocyclic” moiety in the terms    “heterocycliccarbonyl”, “heterocyclic(lower)alkanoyl”,    “heterocyclic(lower)alkenoyl” and “heterocyclicglyoxyloyl” can be    referred to aforementioned “heterocyclic” moiety, and this “acyl    group” may have one or more suitable substituent(s) selected from    the group consisting of lower alkyl, oxo, amino and hydroxy.

Suitable example of “acyl group” of R¹ can be referred to aforementioned“acyl group”, in which the preferred one may be aroyl which may have oneor more suitable substituent(s), lower alkoxycarbonyl, higher alkanoyland heterocycliccarbonyl which may have one or more suitablesubstituent(s).

Suitable example of “suitable substituent(s)” in the term of “aroylsubstituted with one or more suitable substituent(s)” and“heterocycliccarbonyl which may have one or more suitablesubstituent(s)” may be heterocyclic group substituted with aryl havinglower alkoxy, heterocyclic group substituted with aryl having loweralkoxy(lower)alkoxy, heterocyclic group substituted with aryl havinglower alkoxy(higher)alkoxy, heterocyclic group substituted with arylhaving cyclo(lower)alkyloxy, heterocyclic group substituted with arylhaving heterocyclic group, heterocyclic group substituted withcyclo(lower)alkyl having cyclo(lower)alkyl, heterocyclic groupsubstituted with aryl having aryl substituted with loweralkoxy(lower)alkoxy, heterocyclic group substituted with aryl havingheterocyclic group substituted with cyclo(lower)alkyl, heterocyclicgroup substituted with aryl having aryl substituted with heterocyclicgroup, heterocyclic group substituted with aryl having aryl substitutedwith lower alkoxy(lower)alkyl, heterocyclic group substituted with arylhaving heterocyclic group substituted with aryl(lower)alkoxy,heterocyclic group substituted with aryl having heterocyclic groupsubstituted with lower alkoxy and aryl having halogen, heterocyclicgroup substituted with aryl having aryl substituted with lower alkoxy,heterocyclic group substituted with aryl having cyclo(lower)alkyl,heterocyclic group substituted with aryl having heterocyclic groupsubstituted with aryl, heterocyclic group substituted with aryl havingheterocyclic group substituted with aryloxy, heterocyclic groupsubstituted with aryl having heterocyclic group substituted with loweralkoxy(lower)alkoxy, heterocyclic group substituted with aryl is havingheterocyclic group substituted with lower alkoxy(lower)alkylthio,heterocyclic group substituted with aryl having heterocyclic higheralkoxy, heterocyclic group substituted with aryl having heterocyclicgroup substituted with cyclo(lower)alkyloxy, heterocyclic groupsubstituted with aryl having heterocyclic group substituted with arylhaving lower alkoxy(lower)alkoxy, heterocyclic group substituted witharyl having aryloxy(lower)alkoxy, heterocyclic group substituted witharyl having heterocyclic group substituted with lower alkylthio,heterocyclic group substituted with aryl having heterocyclic groupsubstituted with lower alkoxy and aryl, aryl substituted withheterocyclic group having aryl substituted with heterocyclic group, arylsubstituted with lower alkoxy having cyclo(lower)alkyl and amino, arylsubstituted with heterocyclic group having cyclo(lower)alkyl, arylsubstituted with lower alkoxy having cyclo(lower)alkyl and protectedamino, aryl substituted with heterocyclic group having lower alkyl, arylsubstituted with aryl having lower alkoxy, heterocyclic groupsubstituted with cyclo(lower)alkyl having lower alkyl, heterocyclicgroup substituted with cyclo(lower)alkyl having lower alkoxy andcyclo(lower)alkyl, heterocyclic group substituted with cyclo(lower)alkylhaving cyclo(lower)alkyl substituted with lower alkoxy, heterocyclicgroup substituted with aryl having lower alkoxy(lower)alkylsulfonyl,heterocyclic group substituted with aryl having loweralkoxy(higher)alkylsulfonyl, higher alkoxy, aryl substituted with loweralkoxy(higher)alkoxy, heterocyclic group substituted with aryl havinghigher alkoxy, heterocyclic group substituted with higher alkyl, inwhich the preferred one may be unsaturated condensed heterocyclic groupcontaining 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substitutedwith phenyl having (C₄-C₆)alkoxy, unsaturated 3 to 8-memberedheteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s) substituted with phenyl having(C₁-C₄)alkoxy(C₄-C₆)alkoxy, unsaturated 3 to 8-membered heteromonocyclicgroup containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s)substituted with phenyl having (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy, saturated 3to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)substituted with phenyl having (C₁-C₄)alkoxy(C₇-C₁₄₎alkoxy, unsaturatedcondensed heterocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s) substituted with phenyl having cyclo(C₄-C₆)alkyloxy,unsaturated condensed heterocyclic group containing 1 or 2 sulfuratom(s) and 1 to 3 nitrogen atom(s) substituted with phenyl havingsaturated 3 to 8-membered heteromonocyclic group containing 1 or 2oxygen atom(s) and 1 to 3 nitrogen atom(s), saturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s) substitutedwith cyclo(C₄-C₆)alkyl having cyclo(C₄-C₆)alkyl, unsaturated 3 to8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1to 3 nitrogen atom(s) substituted with phenyl having phenyl substitutedwith (C₁-C₄)alkoxy(C₁-C₄)alkoxy, unsaturated 3 to 8-memberedheteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3nitrogen atom(s) substituted with phenyl having saturated 3 to8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)substituted with cyclo(C₄-C₆)alkyl, unsaturated condensed heterocyclicgroup containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s)substituted with phenyl having saturated 3 to 8-memberedheteromonocyclic group containing 1 to 4 nitrogen atom(s) havingcyclo(C₄-C₆)alkyl,

-   -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having (C₄-C₆)alkoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having cyclo(C₄-C₆)alkyl,    -   unsaturated 3 to 9-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having phenyl substituted with (C₁-C₄)alkoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having phenyl substituted with (C₁-C₄₎alkoxy(C₁-C₄₎alkyl,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having phenyl substituted with saturated 3 to 8-membered        heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to        3 nitrogen atom(s) having di(C₁-C₄)alkyl,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group        containing 1 to 4 nitrogen atom(s) substituted with        cyclo(C₄-C₆₎alkyl,having (C₁-C₄₎alkyl,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group        containing 1 to 4 nitrogen atom(s) substituted with phenyl,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group        containing 1 to 4 nitrogen atom(s) substituted with phenoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group        containing 1 to 4 nitrogen atom(s) substituted with        phenyl(C₁-C₄)alkoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group        containing 1 to 4 nitrogen atom(s) substituted with        (C₁-C₄)alkoxy and chlorophenyl,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group        containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s)        substituted with di(C₁-C₄)alkyl,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        to 4 nitrogen atom(s) substituted with phenyl having        (C₇-C₁₄)alkoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having (C₄-C₆)alkoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having (C₁-C₄)alkoxy(C₄-C₆)alkoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having (C₇-C₁₄)alkoxy substituted with saturated 3 to        8-membered heteromonocyclic group containing 1 or 2 oxygen        atom(s) and 1 to 3 nitrogen atom(s) having di(C₁-C₄)alkyl,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group        containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s)        substituted with di(C₁-C₄)alkyl,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        or 2 oxygen atom(s) and 1 to 4 nitrogen atom(s) substituted with        phenyl having (C₁-C₄)alkoxy(C₇-C₁₄)alkylsulfonyl,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having        (C₁-C₄)alkoxy(C₄-C₆)alkoxy,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having (C₁-C₄)alkoxy        substituted with phenoxy,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having        cyclo(C₄-C₆)alkyl,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having phenyl        substituted with (C₁-C₄)alkoxy(C₄-C₆)alkoxy,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having phenyl        substituted with saturated 3 to 8-membered heteromonocyclic        group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen        atom(s) substituted with di(C₁-C₄)alkyl,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s) substituted with cyclo(C₄-C₆)alkyloxy,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s) substituted with phenyl,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s) substituted with phenyl having        (C₁-C₄)alkoxy(C₄-C₆)alkoxy,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s) substituted with (C₁-C₄)alkylthio,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s) substituted with (C₁-C₄)alkoxy(C₄-C₆)alkylthio,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s) substituted with cyclo(C₄-C₆)alkyl,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s) substituted with saturated 3 to 8-membered        heteromonocyclic group containing 1 or 2 oxygen atom(s),    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s) substituted with (C₁-C₄)alkoxy and phenyl,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s) substituted with (C₁-C₄)alkoxy and chlorophenyl,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with phenyl having saturated 3 to        8-membered heteromonocyclic group containing 1 or 2 oxygen        atom(s) and 1 to 4 nitrogen atom(s) substituted with        di(C₁-C₄)alkyl,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with cyclo(C₄-C₆)alkyl having        (C₄-C₆)alkyl,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with cyclo(C₄-C₆)alkyl having        cyclo(C₄-C₆)alkyl and (C₁-C₄)alkoxy,    -   saturated 3 to 8-membered heteromonocyclic group containing 1 to        4 nitrogen atom(s) substituted with cyclo(C₄-C₆)alkyl having        cyclo(C₄-C₆)alkyl substituted with (C₁-C₄)alkoxy,    -   unsaturated condensed heterocyclic group containing 1 or 2        sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having (C₁-C₄)alkoxy(C₄-C₆)alkoxy,    -   unsaturated condensed heterocyclic group containing 1 or 2        sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group 1        to 4 nitrogen atom(s) substituted with        (C₁-C₄)alkoxy(C₁-C₆)alkoxy,    -   unsaturated condensed heterocyclic group containing 1 or 2        sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group 1        to 4 nitrogen atom(s) substituted with        (C₁-C₄)alkoxy(C₄-C₆)alkylthio,    -   unsaturated condensed heterocyclic group containing 1 or 2        sulfur atom(s) and 1 to 3 nitrogen atom(s) substituted with        phenyl having saturated 3 to 8-membered heteromonocyclic group 1        or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) substituted with        di(C₁-C₄)alkyl,    -   phenyl substituted with (C₁-C₄)alkoxy having cyclo(C₄-C₆)alkyl        and protected amino,    -   phenyl substituted with (C₁-C₄)alkoxy having cyclo(C₄-C₆)alkyl        and amino,    -   phenyl substituted with phenyl having (C₄-C₆)alkoxy,    -   phenyl substituted with unsaturated 3 to 8-membered        heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to        3 nitrogen atom(s) having (C₄-C₆)alkyl,    -   phenyl substituted with saturated 3 to 8-membered        heteromonocyclic group containing 1 to 4 nitrogen atom(s)        substituted with cyclo(C₄-C₆)alkyl,    -   phenyl substituted with saturated 3 to 8-membered        heteromonocyclic group containing 1 to 4 nitrogen atom(s) having        phenyl substituted with saturated 3 to 8-membered        heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to        3 nitrogen atom(s) having di(C₁-C₄)alkyl,    -   phenyl substituted with condensed heterocyclic group containing        1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) having        (C₄-C₆)alkyl, (C₇-C₁₄)alkoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        to 4 nitrogen atom(s) substituted with (C₇-C₁₄)alkyl,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        to 4 nitrogen atom(s) substituted with phenyl having        (C₄-C₆)alkoxy,    -   unsaturated 3 to 8-membered heteromonocyclic group containing 1        to 4 nitrogen atom(s) substituted with phenyl having saturated 3        to 8-membered heteromonocyclic group containing 1 to 4 nitrogen        atom(s),    -   xylyl substituted with (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy, and the most        preferred one may be imidazothiadiazolyl substituted with phenyl        having pentyloxy, thiadiazolyl substituted with phenyl having        methoxyhexyloxy, thiadiazolyl substituted with phenyl having        methoxyoctyloxy, thiadiazolyl substituted with phenyl having        methoxyheptyloxy, imidazothiadiazolyl substituted with phenyl        having cyclohexyloxy, imidazothiadiazolyl substituted with        phenyl having dimethylmorpholino, piperazinyl substituted with        phenyl having methoxyheptyloxy, piperazinyl substituted with        phenyl having methoxyoctyloxy, piperazinyl substituted with        cyclohexyl having cyclohexyl, thiadiazolyl substituted with        phenyl having phenyl substituted with methoxyethoxy,        thiadiazolyl substituted with phenyl having phenyl substituted        with methoxybutoxy, thiadiazolyl substituted with phenyl having        phenyl substituted with ethoxypropoxy, imidazothiadiazolyl        substituted with phenyl having piperazinyl substituted with        cyclohexyl, imidazothiadiazolyl substituted with phenyl having        piperazinyl substituted with cyclohexyl,    -   thiazolyl substituted with phenyl having pentyloxy,    -   thiadiazolyl substituted with phenyl having methoxyheptyloxy,    -   thiadiazolyl substituted with phenyl having cyclohexyl,    -   thiadiazolyl substituted with phenyl having cyclohexyloxy,    -   thiadiazolyl substituted with phenyl having phenyl substituted        with propoxy,    -   thiadiazolyl substituted with phenyl having phenyl substituted        with ethoxymethyl,    -   thiadiazolyl substituted with phenyl having phenyl substituted        with methoxypropoxy,    -   thiadiazolyl substituted with phenyl having piperazinyl        substituted with cyclohexyl,    -   thiadiazolyl substituted with phenyl having phenyl substituted        with dimethylmorpholino,    -   thiadiazolyl substituted with phenyl having piperazinyl        substituted with methylcyclohexyl,    -   thiadiazolyl substituted with phenyl having piperidyl,    -   thiadiazolyl substituted with phenyl having piperidyl        substituted with phenyl,    -   thiadiazolyl substituted with phenyl having piperidyl        substituted with phenoxy,    -   thiadiazolyl substituted with phenyl having piperidyl        substituted with benzyloxy,    -   thiadiazolyl substituted with phenyl having piperidyl        substituted with methoxy and chlorophenyl,    -   thiadiazolyl substituted with phenyl having dimethylmorpholino,    -   pyrimidinyl substituted with phenyl having octyloxy,    -   isoxazolyl substituted with phenyl having pentyloxy,    -   isoxazolyl substituted with phenyl having methoxyhexyloxy,    -   isosxazolyl substituted with phenyl having methoxyheptyloxy,    -   isoxazolyl substituted with phenyl having heptyloxy substituted        with dimethylmorpholino,    -   isoxazolyl substituted with phenyl having octyloxy substituted        with dimethylmorpholino,    -   isoxazolyl substituted with phenyl having dimethylmorpholino,    -   oxadiazolyl substituted with phenyl having pentyloxy,    -   oxadiazolyl substituted with phenyl having methoxyheptyloxy,    -   oxadiazolyl substituted with phenyl having methoxynonyloxy,    -   oxadiazolyl substituted with phenyl having        methoxyheptylsulfonyl,    -   oxadiazolyl substituted with phenyl having methoxynonylsulfonyl,    -   piperazinyl substituted with phenyl having methoxyhexyloxy,    -   piperazinyl substituted with phenyl having methoxyheptyloxy,    -   piperazinyl substituted with phenyl having phenoxypropoxy,    -   piperazinyl substituted with phenyl having cyclohexyl,    -   piperazinyl substituted with phenyl having phenyl substituted        with methoxypentyloxyphenyl,    -   piperazinyl substituted with phenyl having phenyl substituted        with dimethylmorpholino,    -   piperazinyl substituted with phenyl having piperidyl substituted        with cyclohexyloxy,    -   piperazinyl substituted with phenyl having piperidyl substituted        with phenyl,    -   piperazinyl substituted with phenyl having piperidyl substituted        with methoxybutoxyphenyl,    -   piperazinyl substituted with phenyl having piperidyl substituted        with propylthio,    -   piperazinyl substituted with phenyl having piperidyl substituted        with methoxyhexylthio,    -   piperazinyl substituted with phenyl having piperidyl substituted        with cyclobutanespiro,    -   piperazinyl substituted with phenyl having piperidyl substituted        with dioxacyclobutanespiro,    -   piperazinyl substituted with phenyl having piperidyl substituted        with methoxy and phenyl,    -   piperazinyl substituted with phenyl having piperidyl substituted        with methoxy and chlorophenyl,    -   piperazinyl substituted with phenyl having dimethylmorpholino,    -   piperazinyl substituted with cyclohexyl having tert-butyl,    -   piperazinyl substituted with cyclohexyl having cyclohexyl and        methoxy,    -   piperazinyl substituted with cyclohexyl having cyclohexyl        substituted with propoxy,    -   imidazothiadiazolyl substituted with phenyl having        methoxybutoxy,    -   imidazolthiadiazolyl substituted with phenyl having        cyclohexyloxy,    -   imidazothiadiazolyl substituted with phenyl having piperazinyl        substituted with cyclohexyl,    -   imidazolthiadiazolyl substituted with phenyl having piperidyl        substituted with methoxypropoxy,    -   imidazothiadiazolyl substituted with phenyl having piperidyl        substituted with methoxybutoxy,    -   imidazothiadiazolyl substituted with phenyl having piperidyl        substituted with methoxypentyloxy,    -   imidazothiadiazolyl substituted with phenyl having piperidyl        substituted with methoxyhexyloxy,    -   imidazothiadiazolyl substituted with phenyl having piperidyl        substituted with methoxyhexylthio,    -   imidazothiadiazolyl substituted with phenyl having        dimethylmorpholino,    -   phenyl substituted with propoxy having cyclohexyl and        tert-butoxycarbonylamino,    -   phenyl substituted with propoxy having cyclohexyl and amino,    -   phenyl substituted with phenyl having pentyloxy,    -   phenyl substituted with thiazolyl having pentyl,    -   phenyl substituted with piperazinyl having cyclohexyl,    -   phenyl substituted with piperazinyl having phenyl substituted        with dimethylmorpholino,    -   phenyl substituted with bezoxazolyl having pentyl, octyloxy,    -   pyrazolyl substituted with decyl,    -   pyrazolyl substituted with phenyl having hexyloxy,    -   pyrazolyl substituted with phenyl having piperidyl,    -   xylyl substituted with methoxyheptyloxy.

The more suitable example of “acyl group” may be benzoyl which hasimidazolthiadiazolyl substituted with phenyl having pentyloxy, benzoylwhich has thiadiazolyl substituted with phenyl having methoxyhexyloxy,benzoyl which has thiadiazolyl substituted with phenyl havingmethoxyoctyloxy, benzoyl which has thiadiazolyl substituted with phenylhaving methoxyheptyloxy, benzoyl which has imidazothiadiazolylsubstituted with phenyl having cyclohexyloxy, benzoyl which hasimidazothiadiazolyl substituted with phenyl having dimethylmorpholino,benzoyl which has piperazinyl substituted with phenyl havingmethoxyheptyloxy, benzoyl which has piperazinyl substituted with phenylhaving methoxyoctyloxy, benzoyl which has piperazinyl substituted withcyclohexyl having cyclohexyl, benzoyl which has thiadiazolyl substitutedwith phenyl having phenyl substituted with methoxyethoxy, benzoyl whichhas thiadiazolyl substituted with phenyl having phenyl substituted withmethoxybutoxy, benzoyl which has thiadiazolyl substituted with phenylhaving phenyl substituted with ethoxypropoxy, benzoyl which hasimidazothiadiazolyl substituted with phenyl having piperazinylsubstituted with cyclohexyl, benzoyl which has imidazothiadiazolylsubstituted with phenyl having piperazinyl substituted with cyclohexyl,

-   -   benzoyl which has thiazolyl substituted with phenyl having        pentyloxy,    -   benzoyl which has thiadiazolyl substituted with phenyl having        methoxyheptyloxy,    -   benzoyl which has thiadiazolyl substituted with phenyl having        cyclohexyl,    -   benzoyl which has thiadiazolyl substituted with phenyl having        cyclohexyloxy,    -   benzoyl which has thiadiazolyl substituted with phenyl having        phenyl substituted with propoxy,    -   benzoyl which has thiadiazolyl substituted with phenyl having        phenyl substituted with ethoxymethyl,    -   benzoyl which has thiadiazolyl substituted with phenyl having        phenyl substituted with methoxypropoxy,    -   benzoyl which has thiadiazolyl substituted with phenyl having        phenyl substituted with dimethylmorpholino,    -   benzoyl which has thiadiazolyl substituted with phenyl having        piperazinyl substituted with cyclohexyl,    -   benzoyl which has thiadiazolyl substituted with phenyl having        piperazinyl substituted with methylcyclohexyl,    -   benzoyl which has thiadiazolyl substituted with phenyl having        piperidyl,    -   benzoyl which has thiadiazolyl substituted with phenyl having        piperidyl substituted with phenyl,    -   benzoyl which has thiadiazolyl substituted with phenyl having        piperidyl substituted with phenoxy,    -   benzoyl which has thiadiazolyl substituted with phenyl having        piperidyl substituted with benzyloxy,    -   benzoyl which has thiadiazolyl substituted with phenyl having        piperidyl substituted with methoxy and chlorophenyl,    -   benzoyl which has thiadiazolyl substituted with phenyl having        dimethylmorpholino,    -   benzoyl which has pyrimidinyl substituted with phenyl having        octyloxy,    -   benzoyl which has isoxazolyl substituted with phenyl having        pentyloxy,    -   benzoyl which has isoxazolyl substituted with pentyl having        methoxyhexyloxy,    -   benzoyl which has isoxazolyl substituted with phenyl having        methoxyheptyloxy,    -   benzoyl which has isoxazolyl substituted with phenyl having        heptyloxy substituted with dimethylmorpholino,    -   benzoyl which has isoxazolyl substituted with phenyl having        octyloxy substituted with dimethylmorpholino,    -   benzoyl which has isoxazolyl substituted with phenyl having        dimethylmorpholino,    -   benzoyl which has oxadiazolyl substituted with phenyl having        pentyloxy,    -   benzoyl which has oxadiazolyl substituted with phenyl having        methoxyheptyloxy,    -   benzoyl which has oxadiazolyl substituted with phenyl having        methoxynonyloxy,    -   benzoyl which has oxadiazolyl substituted with phenyl having        methoxyheptylsulfonyl,    -   benzoyl which has oxadiazolyl substituted with phenyl having        methoxynonylsulfonyl,    -   benzoyl which has piperazinyl substituted with phenyl having        methoxyhexyloxy,    -   benzoyl which has piperazinyl substituted with phenyl having        methoxyheptyloxy,    -   benzoyl which has piperazinyl substituted with phenyl having        phenoxypropoxy,    -   benzoyl which has piperazinyl substituted with phenyl having        cyclohexyl,    -   benzoyl which has piperazinyl substituted with phenyl having        phenyl substituted with methoxypentyloxyphenyl,    -   benzoyl which has piperazinyl substituted with phenyl having        phenyl substituted with dimethylmorpholino,    -   benzoyl which has piperazinyl substituted with phenyl having        piperidyl substituted with cyclohexyloxy,    -   benzoyl which has piperazinyl substituted with phenyl having        piperidyl substituted with phenyl,    -   benzoyl which has piperazinyl substituted with phenyl having        piperidyl substituted with methoxybutoxyphenyl,    -   benzoyl which has piperazinyl substituted with phenyl having        piperidyl substituted with propylthio,    -   benzoyl which has piperazinyl substituted with phenyl having        piperidyl substituted with methoxyhexylthio,    -   benzoyl which has piperazinyl substituted with phenyl having        piperidyl substituted with cyclobutanespiro,    -   benzoyl which has piperazinyl substituted with phenyl having        piperidyl substituted with dioxacyclobutanespiro,    -   benzoyl which has piperazinyl substituted with phenyl having        piperidyl substituted with methoxy and phenyl,    -   benzoyl which has piperazinyl substituted with phenyl having        piperidyl substituted with methoxy and chlorophenyl,    -   benzoyl which has piperazinyl substituted with phenyl having        dimethylmorpholino,    -   benzoyl which has piperazinyl substituted with cyclohexyl having        tert-butyl,    -   benzoyl which has piperazinyl substituted with cyclohexyl having        cyclohexyl and methoxy,    -   benzoyl which has piperazinyl substituted with cyclohexyl having        cyclohexyl substituted with propoxy,    -   benzoyl which has imidazothiadiazolyl substituted with phenyl        having methoxybutoxy,    -   benzoyl which has imidazothiadiazolyl substituted with phenyl        having cyclohexyloxy,    -   benzoyl which has imidazothiadiazolyl substituted with phenyl        having piperazinyl substituted with cyclohexyl,    -   benzoyl which has imidazothiadiazolyl substituted with phenyl        having piperidyl substituted with methoxypropoxy,    -   benzoyl which has imidazothiadiazolyl substituted with phenyl        having piperidyl substituted with methoxybutoxy,    -   benzoyl which has imidazothiadiazolyl substituted with phenyl        having piperidyl substituted with methoxypentyloxy,    -   benzoyl which has imidazothiadiazolyl substituted with phenyl        having piperidyl substituted with methoxyhexyloxy,    -   benzoyl which has imidazothiadiazolyl substituted with phenyl        having piperidyl substituted with methoxyhexylthio,    -   benzoyl which has imidazothiadiazolyl substituted with phenyl        having dimethylmorpholino,    -   benzoyl which has phenyl substituted with propoxy having        cyclohexyl and tert-butoxycarbonylamino,    -   benzoyl which has phenyl substituted with propoxy having        cyclohexyl and amino,    -   benzoyl which has phenyl substituted with phenyl having        pentyloxy,    -   benzoyl which has phenyl substituted with thiazolyl having        pentyl,    -   benzoyl which has phenyl substituted with piperazinyl having        cyclohexyl,    -   benzoyl which has phenyl substituted with piperazinyl having        phenyl substituted with dimethylmorpholino,    -   benzoyl which has phenyl substituted with benzoxazolyl having        pentyl,    -   benzoyl which has octyloxy,    -   thiadiazolylcarbonyl which has pyrazolyl substituted with decyl,    -   thiadiazolylcarbonyl which has pyrazolyl substituted with phenyl        having hexyloxy,    -   thiadiazolylcarbonyl which has pyrazolyl substituted with phenyl        having piperidyl,    -   piperazinylcarbonyl which has xylyl substituted with        methoxyheptyloxy, palmitoyl.

Suitable example of “lower alkyl” in the term of “lower alkyl which mayhave one or more suitable substituent(s)” can be referred toaforementioned “lower alkyl”.

Suitable example of “suitable substituent(s)” in the term of “loweralkyl which may have one or more suitable substituent(s)” may be imino,amino, carbamoyl, lower alkoxy, heterocyclic group which may have one ormore lower alkyl, carboxy, cyano(lower)alkylidene, lower alkylthio,sulfonic acid group, hydroxysulfonyloxy, and the like, in which thepreferred one may be imino, amino, carbamoyl, lower alkoxy, pyrazolylwhich may have lower alkyl, carboxy, hydroxy(lower)alkylamino which mayhave hydroxy(lower)alkyl, cyano(lower)alkylidene, lower alkylthio,sulfonic acid group or hydroxysulfonyloxy, and the more preferred onemay be imino, amino, carbamoyl, methoxy, pyrazolyl which may havemethyl, carboxy, hydroxyethylamino which may have hydroxymethyl,cyanomethylidene, sulfonic acid group or hydroxysulfonyloxy.

Suitable example of “lower alkyl which may have one or more suitablesubstituent(s)” may be iminomethyl, 1-iminoethyl, amidino,1-imino-2-carbamoylethyl, 1-imino-3-methoxypropyl, carboxymethyl,3-aminopropyl, 1-methylpyrazol-4-ylmethyl, methyl, pyrazolylmethylhaving methyl, aminopropyl, aminobutyl, aminopentyl, carboxypentyl,carboxymethyl, cyanomethylidenemethylthiomethyl,2-cyano-1-methylthiovinyl, 2-cyano-1-aminovinyl, sulfopropyl,sulfobutyl, hydroxysulfonyloxypropyl and carboxyethyl.

Suitable example of “acyl group” of R² and R³ can be referred toaforementioned “acyl group”, in which the preferred one may be loweralkanoyl, ar(lower)alkoxycarbonyl, lower alkenyloxycarbonyl, loweralkoxycarbonyl which may have lower alkanoyloxy,heterocyclic(lower)alkoxycarbonyl which may have oxo and lower alkyl,amino(lower)alkanoyl which may have amino or hydroxy,heterocyclic(lower)alkanoyl which may have amino, sulfonic acid group,heterocycliccarbonyl, mono or di lower alkylcarbamoyl, and the mostpreferred one may be acetyl, sulfo, 2,5-diaminopentanoyl,fluorenylmethoxycarbonyl, allyloxycarbonyl, tert-butoxycarbonyl,1,3-dioxy-2-oxo-4-methyl-4-cyclopenten-5-ylmethoxycarbonyl,acetyloxymethoxycarbonyl, aminopropionyl, aminopentanoyl, aminohexanoyl,5-amino-2-hydroxybutanoyl, 2,6-diaminohexanoyl,2-amino-3-(pyrazol-4-yl)propionyl, morpholinocarbonyl,dimethylcarbamoyl, diethylcarbamoyl or pyrrolidin-1-ylcarbonyl.

Suitable example of “suitable substituent(s)” in the term of“heterocyclic group which may have one or more suitable substituent(s)”of R² and R³ may be lower alkyl, hydroxy(lower)alkyl,carboxy(lower)alknonoyl which may have amino and heterocycliccarbonyl,cyclo(lower)alkyl, oxo, and the like.

Suitable example of “heterocyclic group which may have one or moresuitable substituent(s)” of R² and R³ may be piperidyl which may haveone or more suitable substituent(s) selected from the group consistingof lower alkyl, hydroxy(lower)alkyl, carboxy(lower)alkanoyl which mayhave amino and heterocycliccarbonyl; 1,3-dioxacyclohexyl which may haveone or more suitable substituent(s) selected from the group consistingof lower alkyl and cyclo(lower)alkyl; thiopyranyl which may have one ormore oxo; in which the most preferred one may be N,N-dimethylpiperidyl,N-hydroxyethyl-N-methylpiperidyl, carboxypropanoylpiperidyl,4-amino-4-carboxybutanoylpiperidyl, azetidinylcarbonylpiperidyl,dimethyl-1,3-dioxacyclohexyl, cyclohexyl-1,3-dioxacyclohexyl,dioxopyranyl.

Suitable example of “lower alkylidene which may have one or moresuitable substituent(s)” of R² and R³ may be lower alkylidene which mayhave one or more lower alkylamino, in which the preferred one may bedimethylaminomethylidene.

Suitable example of “higher alkyl which may have one or more suitablesubstituent(s)” of R² and R³ may be higher alkyl which may have one ormore carboxy, in which the preferred one may be carboxyoctyl.

Suitable example of “acyl” moiety of “acyloxy” can be referred toaforementioned “acyl group”, in which the preferred one may be loweralkenyloxycarbonyl, and the most preferred one may be allyloxycarbonyl.

Suitable example of “acyloxy” may be lower alkenyloxycarbonyloxy, andthe more preferred one may be allyloxycarbonyloxy.

Suitable example of “amino protective group” may be included inaforementioned “acyl group”, a conventional protective group such asar(lower)alkoxycarbonyl and lower alkoxycarbonyl, in which the preferredone may be phenyl(C₁-C₄)alkoxycarbonyl andfluorenyl(C₁-C₄)alkoxycarbonyl and (C₁-C₄)alkoxycarbonyl, and the mostpreferred one may be benzyloxycarbonyl, fluorenylmethoxycarbonyl andtert-butoxycarbonyl.

Suitable example of “protected amino” may be amino substituted withaforementioned “acyl group”, a conventional protected amino such asar(lower)alkoxycarbonylamino and lower alkoxycarbonylamino, in which thepreferred one may be phenyl(C₁-C₄)alkoxycarbonylamino andfluorenyl(C₁-C₄)alkoxycarbonylamino and (C₁-C₄)alkoxycarbonylamino, andthe most preferred one may be benzyloxycarbonylamino,fluorenylmethoxycarbonylamino and tert-butoxycarbonylamino.

Particularly, the preferred examples of the compound (I) in the presentinvention are as follows: the compound (I), wherein

-   -   R¹ is hydrogen; lower alkoxycarbonyl;        -   aroyl which has heterocyclic group substituted with aryl            having a suitable substituent selected from the group            consisting of lower alkoxy, lower alkoxy(lower)alkoxy, lower            alkoxy(higher)alkoxy, aryl substituted with lower            alkoxy(lower)alkoxy, cyclo(lower)alkyl,            cyclo(lower)alkyloxy, aryl substituted with lower alkoxy,            aryl substituted with lower alkoxy(lower)alkyl, aryl            substituted with heterocyclic group, heterocyclic group            substituted with cyclo(lower)alkyl, heterocyclic group,            heterocyclic group substituted with aryl, heterocyclic group            substituted with aryloxy, heterocyclic group substituted            with ar(lower)alkoxy, heterocyclic group substituted with            lower alkoxy and aryl, higher alkoxy,            heterocyclic(higher)alkoxy, lower            alkoxy(higher)alkylsulfonyl, aryloxy(lower)alkoxy,            heterocyclic group substituted with cyclo(lower)alkyloxy,            heterocyclic group substituted with aryl having lower            alkoxy(lower)alkoxy, heterocyclic group substituted with            lower alkylthio, heterocyclic group substituted with lower            alkoxy(lower)alkylthio, and heterocyclic group substituted            with lower alkoxy(lower)alkoxy;        -   aroyl which has aryl substituted with a suitable substituent            selected from the group consisting of lower alkoxy having            cyclo(lower)alkyl and amino, lower alkoxy having            cyclo(lower)alkyl and protected amino, aryl having lower            alkoxy, heterocyclic group having lower alkyl, heterocyclic            group having cyclo(lower)alkyl, and heterocyclic group            having aryl substituted with heterocyclic group;        -   aroyl which has heterocyclic group substituted with            cyclo(lower)alkyl having one or more suitable substituent(s)            selected from the group consisting of lower alkyl, lower            alkoxy, cyclo(lower)alkyl, and cyclo(lower)alkyl substituted            with lower alkoxy;        -   higher alkanoyl;        -   aroyl which has higher alkoxy; or        -   heterocycliccarbonyl which has a suitable substituent(s)            selected from the group consisting of heterocyclic group            substituted with higher alkyl, heterocyclic group            substituted with aryl having lower alkoxy, heterocyclic            group substituted with aryl having heterocyclic group, and            aryl substituted with lower alkoxy(higher)alkoxy,    -   R² and R³ are independently hydrogen;        -   lower alkyl which may have one or more suitable            substituent(s) selected from the group consisting of amino,            carboxy, sulfinic acid group, sulfonic acid group,            hydroxy(lower)alkylamino which may have hydroxy(lower)alkyl,            hydroxysulfonyloxy, imino, lower alkoxy, oxo, lower            alkylthio, cyano(lower)alkylidene, and heterocyclic group            which may have one or more lower alkyl;        -   lower alkoxycarbonyl which may have one or more suitable            substituent(s) selected from the group consisting of lower            alkanoyloxy and heterocyclic group;        -   lower alkenyloxycarbonyl;        -   ar(lower)alkoxycarbonyl;        -   lower alkanoyl which may have one or more suitable            substituent(s) selected from the group consisting of amino,            hydroxy and heterocyclic group;        -   heterocycliccarbonyl;        -   mono or di(lower)alkylcarbamoyl;        -   sulfonic acid group;        -   heterocyclic group which may have one or more suitable            substituent(s) selected from the group consisting of lower            alkyl, hydroxy(lower)alkyl, carboxy(lower)alkanoyl which may            have amino, heterocycliccarbonyl, cyclo(lower)alkyl, and            oxo;        -   lower alkylidene which may have mono or di lower alkylamino;        -   carboxy(higher)alkyl or        -   cyano;    -   R⁴ is hydrogen or hydroxy;    -   R⁵ is hydrogen, hydroxy, lower alkoxy or hydroxysulfonyloxy; and    -   R⁶ is hydroxy or lower alkenyloxycarbonyloxy, the more preferred        one is the compound (I), wherein    -   R¹ is hydrogen; (C₁-C₄)alkoxycarbonyl;        -   benzoyl which has thiazolyl substituted with phenyl having            (C₄-C₆)alkoxy;        -   benzoyl which has thiadiazolyl substituted with phenyl            having a suitable substituent selected from the group            consisting of (C₁-C₄)alkoxy(C₄-C₆)alkoxy, phenyl substituted            with (C₁-C₄)alkoxy(C₁-C₄)alkoxy,            (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy, cyclo(C₄-C₆)alkyl,            cyclo(C₄-C₆)alkyloxy, phenyl substituted with (C₁-C₄)alkoxy,            phenyl substituted with (C₁-C₄)alkoxy(C₁-C₄)alkyl, phenyl            substituted with di(C₁-C₄)alkylmorpholino, piperazinyl            substituted with cyclo(C₄-C₆)alkyl, piperazinyl substituted            with cyclo(C₄-C₆)alkyl having (C₁-C₄)alkyl; piperidyl,            piperidyl substituted with phenyl, piperidyl substituted            with phenoxy, piperidyl substituted with benzyloxy,            piperidyl substituted with (C₁-C₄)alkoxy and chlorophenyl,            and phenyl having di(C₁-C₄)alkylmorpholino;        -   benzoyl which has pyrimidinyl substituted with phenyl having            (C₇-C₁₄)alkoxy;        -   benzoyl which has isoxazolyl substituted with phenyl having            a suitable substituent selected from the group consisting of            (C₄-C₆)alkoxy, (C₁-C₄)alkoxy(C₄-C₆)alkoxy,            (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy, (C₇-C₁₄)alkoxy substituted with            di(C₁-C₄)alkylmorpholino, and di(C₁-C₄)alkylmorpholino;        -   benzoyl which has oxadiazolyl substituted with phenyl having            a suitable substituent selected from the group consisting of            (C₄-C₆)alkoxy, (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy,            (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy, and            (C₁-C₄)alkoxy(C₇-C₁₄)alkylsulfonyl;        -   benzoyl which has piperazinyl substituted with phenyl having            a suitable substituent selected from the group consisting of            (C₁-C₄)alkoxy(C₄-C₆)alkoxy, (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy,            phenoxy(C₁-C₄)alkoxy, cyclo(C₄-C₆)alkyl, phenyl substituted            with (C₁-C₄)alkoxy(C₄-C₆)alkoxyphenyl, phenyl substituted            with di(C₁-C₄)alkylmorpholino, piperidyl substituted with            cyclo(C₄-C₆)alkyloxy, piperidyl substituted with phenyl,            piperidyl substituted with (C₁-C₄)alkoxy(C₁-C₄)alkoxyphenyl,            piperidyl substituted with (C₁-C₄)alkylthio, piperidyl            substituted with (C₁-C₄)alkoxy(C₄-C₆)alkylthio, piperidyl            substituted with cyclo(C₄-C₆)alkanespiro, piperidyl            substituted with dioxacyclo(C₄-C₆)alkanespiro, piperidyl            substituted with (C₁-C₄)alkoxy and phenyl, piperidyl            substituted with (C₁-C₄)alkoxy and chlorophenyl, and            di(C₁-C₄)alkylmorpholino;        -   benzoyl which has piperazinyl substituted with            cyclo(C₄-C₆)alkyl having a suitable substituent selected            from the group consisting of cyclo(C₄-C₆)alkyl,            (C₄-C₆)alkyl, cyclo(C₄-C₆)alkyl and (C₁-C₄)alkoxy, and            cyclo(C₄-C₆)alkyl substituted with (C₁-C₄)alkoxy;        -   benzoyl which has imidazolthiadiazolyl substituted with            phenyl having a suitable substituent selected from the group            consisting of (C₄-C₆)alkoxy, (C₁-C₄)alkoxy(C₄-C₆)alkoxy,            cyclo(C₄-C₆)alkyloxy, piperazinyl substituted with            cyclo(C₄-C₆)alkyl, piperidyl substituted with            (C₁-C₄)alkoxy(C₁-C₄)alkoxy, piperidyl substituted with            (C₁-C₄)alkoxy(C₄-C₆)alkoxy, piperidyl substituted with            (C₁-C₄₎alkoxy(C₄-C₆)alkylthio, and di(C₁-C₄)alkylmorpholino;        -   benzoyl which has phenyl substituted with a suitable            substituent selected from the group consisting of            (C₁-C₄)alkoxy having cyclo(C₄-C₆)alkyl and            (C₁-C₄)alkoxycarbonylamino, (C₁-C₄)alkoxy having            cyclo(C₄-C₆)alkyl and amino, phenyl having (C₄-C₆)alkoxy,            thiazolyl having (C₄-C₆)alkyl, piperazinyl having            cyclo(C₄-C₆)alkyl, piperazinyl having phenyl substituted            with di(C₁-C₄)alkylmorpholino, and benzoxazolyl having            (C₄-C₆)alkyl;        -   benzoyl which has (C₇-C₁₄)alkoxy;        -   thiadiazolylcarbonyl which has pyrazolyl substituted with a            suitable substituent selected from the group consisting of            (C₇-C₁₄)alkyl, phenyl having (C₄-C₆)alkoxy, and phenyl            having piperidyl;        -   piperazinylcarbonyl which has xylyl substituted with            (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy; or (C₇-C₁₄)alkanoyl;    -   R² and R³ are independently hydrogen;        -   (C₁-C₆)alkyl which may have 1 or 2 suitable substituent(s)            selected from the group consisting of amino, carboxy,            sulfinic acid group, sulfonic acid group,            hydroxy(C₁-C₄)alkylamino which may have hydroxy(C₁-C₄)alkyl,            hydroxysulfonyloxy, imino, (C₁-C₄)alkoxy, oxo,            cyano(C₂-C₄)alkylidene, (C₁-C₄)alkylthio, and pyrazolyl            which may have (C₁-C₄)alkyl;        -   (C₁-C₄)alkoxycarbonyl which may have (C₁-C₄)alkanoyloxy,            dioxacyclo(C₄-C₆)alkenyl which may have oxo, and            (C₁-C₄)alkyl;        -   fluorenyl(C₁-C₄)alkoxycarbonyl;        -   (C₂-C₄)alkenyloxycarbonyl;        -   (C₁-C₆)alkanoyl which may have 1 or 2 suitable            substituent(s) selected from the group consisting of amino,            hydroxy and pyrazolyl;        -   pyrrolidinylcarbonyl;        -   morpholinocarbonyl;        -   mono or di(C₁-C₄)alkylcarbamoyl;        -   sulfonic acid group;        -   piperidyl which may have 1 or 2 suitable substituent(s)            selected from the group consisting of (C₁-C₄)alkyl,            hydroxy(C₁-C₄)alkyl, carboxy(C₁-C₄)alkanoyl which may have            amino, and azetidinylcarbonyl;        -   dioxacyclo(C₄-C₆)alkyl which may have 1 or 2 suitable            substituent(s) selected from the group consisting of            (C₁-C₄)alkyl, and cyclo(C₄-C₆)alkyl;        -   thiopyranyl which may have 1 or 2 oxo;        -   (C₂-C₄)alkylidene which may have mono or            di(C₁-C₄)alkylamino;        -   carboxy(C₇-C₁₄)alkyl or        -   cyano,    -   R⁴ is hydrogen or hydroxy,    -   R⁵ is hydrogen, hydroxy, (C₁-C₄)alkoxy or hydroxysulfonyloxy,        and    -   R⁶ is hydroxy or (C₂-C₄)alkenyloxycarbonyloxy.

Process 1

The object compound (Ia) or a salt thereof can be prepared by reducing acompound (II) or a salt thereof.

Suitable salts of the compounds (Ia) and (II) may be the same as thoseexemplified for the compound (I).

The reaction can be carried out in a conventional manner namely,chemical reduction or catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal [e.g. tin, zinc, iron, etc.] or metallic compound[e.g. chromium chloride, chromium acetate, etc.] and an organic orinorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, hydride transfer reagent such as aluminum hydridecompound (e.g. lithium aluminum hydride, lithiumhydridotri-t-butoxyaluminate, etc.), borohydride compound (e.g. sodiumborohydride, sodium cyanoborohydride, etc.) or the like etc.].

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalyst [e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.], palladium catalyst [e.g., spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium sulfate, palladium on barium carbonate, etc.], nickel catalyst[e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalyst[e.g. reduced cobalt, Raney cobalt, etc.], iron catalyst [e.g. reducediron, Raney iron, etc.], copper catalyst [e.g. reduced copper, Raneycopper, Ullman copper, etc.] or the like.

The reaction of this process is usually carried out in a solvent such aswater, alcohol [e.g. methanol, ethanol, propanol, etc.], acetic acid,diethyl ether, dioxane, tetrahydrofuran, methylene chloride, etc. or amixture thereof.

The reaction is preferably carried out under somewhat milder conditionssuch as under cooling to warming.

It is included within the scope of the present invention that “hydroxy”in R⁴ may be reduced to “hydrogen” during the reaction.

Process 2

The object compound (Ib) or a salt thereof can be prepared by subjectingthe compound (Ia) or a salt thereof to protective reaction of amino.

This protective reaction may include acylation or alkylation reaction ofamino and the like, and can be carried out according to a conventionalmanner such as the one described in Examples or the similar mannersthereto.

Process 3

The object compound (Id) or a salt thereof can be prepared by subjectingthe compound (Ic) or its reactive derivative at the sulfonic acid groupor a salt thereof to hydrolysis reaction of the sulfonic acid group.

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid.

Suitable base may include an inorganic base and an organic base such asan alkali metal [e.g., sodium potassium, etc.], an alkaline earth metal[e.g., magnesium, calcium, etc.], the hydroxide or carbonate orhydrogencarbonate thereof, trialkylamine [e.g. trimethylamine,triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, or thelike.

Suitable acid may include an organic acid [e.g., formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.],and an inorganic acid [e.g., hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].

The elimination using Lewis acid such as trihaloacetic acid [e.g.,trichloroacetic acid, trifluoroacetic acid, etc.], or the likepreferably carried out in the presence of cation trapping agent [e.g.,anisole, phenol, etc.].

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g. methanol, ethanol, isopropyl alcohol, etc.],tetrahydrofuran, dioxane, toluene, methylene chloride, ethylenedichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide orany other organic solvent which do not adversely affect the reaction, orthe mixture thereof.

The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

Process 4

The object compound (If) or a salt thereof can be prepared by subjectinga compound (Ie) or a salt thereof to elimination reaction of aminoprotective group.

This reaction is carried out in accordance with a conventional methodsuch as hydrolysis, reduction or the like.

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid. Suitable base may include an inorganic baseand an organic base such as an alkali metal [e.g. sodium, potassium,etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], thehydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g.trimethylamine, triethylamine, etc.], picoline,1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane,1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.

Suitable acid may include an organic acid [e.g. formic acid, aceticacid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.]and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, hydrogen chloride, hydrogen bromide, etc.]. Theelimination using Lewis acid such as trihaloacetic acid [e.g.trichloroacetic acid, trifluoroacetic acid, etc.] or the like ispreferably carried out in the presence of cation trapping agents [e.g.anisole, phenol, etc.].

The reaction is usually carried out in a solvent such as water, analcohol [e.g. methanol, ethanol, etc.], methylene chloride,tetrahydrofuran, a mixture thereof or any other solvent which does notadversely influence the reaction. A liquid base or acid can be also usedas the solvent. The reaction temperature is not critical and thereaction is usually carried out under cooling to warming.

The reduction method applicable for the elimination reaction may includechemical reduction and catalytic reduction.

Suitable reducing agents to be used in chemical reduction are acombination of metal [e.g. tin, zinc, iron, etc.] or metallic compound[e.g. chromium chloride, chromium acetate, etc.] and an organic orinorganic acid [e.g. formic acid, acetic acid, propionic acid,trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid,hydrobromic acid, etc.].

Suitable catalysts to be used in catalytic reduction are conventionalones such as platinum catalysts [e.g. platinum plate, spongy platinum,platinum black, colloidal platinum, platinum oxide, platinum wire,etc.], palladium catalysts [e.g. spongy palladium, palladium black,palladium oxide, palladium on carbon, colloidal palladium, palladium onbarium, sulfate, palladium on barium carbonate, etc.], nickel catalysts[e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobaltcatalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts[e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reducedcopper, Raney copper, Ullman. copper, etc.] and the like.

The reduction is usually carried out in a conventional solvent whichdoes not adversely influence the reaction such as water, methanol,ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.Additionally, in case that the above-mentioned acids to be used inchemical reduction are in liquid, they can also be used as a solvent.Further, a suitable solvent to be used in catalytic reduction may be theabove-mentioned solvent, and other conventional solvent such as diethylether, dioxane, tetrahydrofuran, etc., or a mixture thereof.

The reaction temperature of this reduction is not critical and thereaction is usually carried out under cooling to warming.

Process 5

The compound (Ig) or a salt thereof can be prepared by reducing thecompound (II) or a salt thereof, and then reacting with the compound(IV) of the formula:R_(c) ³—OH  (IV)

-   -   (wherein R_(c) ³ is acyl group)        or its reactive derivative, or a salt thereof.

Suitable reactive derivative of the compound (IV) may include an acidhalide, an acid anhydride, an activated ester, and the like. Thesuitable example may be an acid chloride; acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid (e.g.,dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.),dialkylphosphorous acid, sulfurous acid, thiosulfuric acid,alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid,etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid(e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyricacid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g.,benzoic acid, etc.); a symmetrical acid anydride; an activated amidewith imidazole, 4-substitutd imidazole, dimethylpyrazole, triazole ortetrazole; an activated ester (e.g., cyanomethyl, ester methoxymethylester, dimethyliminomethyl [(CH₃)₂N⁺═CH—] ester, vinyl ester, propargylester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenylester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenylester, phenylthioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester, etc.); an ester with a N-hydroxy compound (e.g.,N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide,1-hydroxy-6-chloro-1H-benzotriazole, etc.); and the like. These reactivederivatives can optionally be selected from them according to the kindof the compound (IV) to be used.

The reaction is usually carried out in a conventional solvent such aswater, acetone, dioxane, acetonitrile, chloroform, methylene chloride,ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent which donot adversely affect the reaction, or the mixture thereof.

When the compound (IV) is used in free acid form or its salt form in thereaction, the reaction is preferably carried out in the presence of aconventional condensing agent such as N,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morphoinoethylcarbodiimide);N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N′-diisopropylcarboxiimide;N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;N,N-carbonyl-bis(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine, ethoxyacetylene;1-alkoxy-1-chloroethylene; trialkyl phosphite; isopropyl polyphosphate;phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride;thionyl chloride; oxalyl chloride; triphenylphosphite;2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intra-molecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole: so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like.

The reaction may also be carried out in the presence of an organic orinorganic base such as an alkali metal bicarbonate, tri(lower)alkylamine(e.g., triethylamine, diisopropylethylamine, etc.), pyridine,di(lower)alkylaminopyridine (e.g., 4-dimethylaminopyridine, etc.)N-(lower)alkylmorphorine, N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to heating.

Process 6

The object compound (Ii) or a salt thereof can be prepared by reactingthe compound (Ih) or a salt thereof with the compound (V) of theformula:R_(b) ²—OH  (V)

-   -   (wherein R_(b) ² is acyl group)        or its reactive derivative, or a salt thereof.

This reaction can be carried out according to a conventional manner suchas the one described in Process 5, Examples or the similar mannerthereto.

Process 7

The object compound (Ik) or a salt thereof can be prepared by reactingthe compound (Ij) or its reactive derivative at the amino group or asalt thereof with the compound (III) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable reactive derivative at the carboxy group of the compound (III)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like. Suitable examples of the reactivederivatives may be an acid chloride; an acid azide; a mixed acidanhydride with an acid such as substituted phosphoric acid [e.g.,dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid,dibenzylphosphoric acid, halogenated phosphoric acid, etc.],dialkylphosphorous acid, sulfurous acid, thiosuluric acid, sulfuricacid, sulfonic acid [e.g., methanesulfonic acid, etc.], aliphaticcarboxylic acid [e.g., acetic acid, propionic acid, butyric acid,isobutyric acid, pivaric acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid, trichloroacetic acid, etc.]; or aromatic carboxylicacid [e.g., benzoic acid, etc.]; a symmetrical acid anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; oran activated ester [e.g., cyanomethyl ester, methoxymethyl ester,dimethyliminomethyl [(CH₃)₂N⁺═CH—] ester, vinyl ester, propargyl ester,p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,pentachloropentyl ester, mesylphenyl ester, phenylazophenyl ester,phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (III) to beused.

Suitable salts of the compound (III) and its reactive derivative can bereferred to the ones as exemplified for the object compound (I).

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvents may also be used in a mixture with water.

In this reaction, when the compound (III) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N′-diethylcarbodiimide; N,N′-diisopropylcarbodiimide;N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis-(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine, ethoxyacetylene;1-alkoxy-2-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkylhaloformate [e.g., ethyl chloroformate, isopropyl chloroformate, etc.];triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorousoxychloride, methanesulfonyl chloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal carbonate alkali metal bicarbonate,tri(lower)alkylamine (e.g., triethylamine, diisopropylethylamine, etc.),pyridine, di(lower)alkylaminopyridine (e.g., 4-dimethylaminopyridine,etc.) N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or thelike.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

Process A

The object compound (IIa) or a salt thereof can be prepared by reactingthe compound (IIb) or its reactive derivative at the amino group or asalt thereof with the compound (III) or its reactive derivative at thecarboxy group or a salt thereof.

Suitable reactive derivative at the carboxy group of the compound (III)may include an acid halide, an acid anhydride, an activated amide, anactivated ester, and the like.

Suitable examples of the reactive derivatives may be an acid chloride;an acid azide; a mixed acid anhydride with an acid such as substitutedphosphoric acid [e.g., dialkylphosphoric acid, phenylphosphoric acid,diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoricacid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulturic acid,sulfuric acid, sulfonic acid [e.g., methanesulfonic acid, etc.],aliphatic carboxylic acid [e.g., acetic acid, propionic acid, butyricacid, isobutyric acid, pivaric acid, pentanoic acid, isopentanoic acid,2-ethylbutyric acid trichloroacetic acid, etc.]; or aromatic carboxylicacid [e.g., benzoic acid, etc.]; a symmetrical acid, anhydride; anactivated amide with imidazole, 4-substituted imidazole,dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; oran activated ester [e.g., cyanomethyl ester, methoxymethyl ester,dimethyliminomethyl [(CH₃)₂N⁺═CH—] ester, vinyl ester, propargyl ester,p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,pentachloropentyl ester, mesylphenyl ester, phenylazophenyl ester,phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester,8-quinolyl thioester, etc.], or an ester with a N-hydroxy compound [e.g.N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole,etc.], and the like. These reactive derivatives can optionally beselected from them according to the kind of the compound (III) to beused.

Suitable salts of the compound (III) and its reactive derivative can bereferred to the ones as exemplified for the object compound (I).

The reaction is usually carried out in a conventional solvent such aswater, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane,acetonitrile, chloroform, methylene chloride, ethylene chloride,tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or anyother organic solvent which does not adversely influence the reaction.These conventional solvent may also be used in a mixture with water.

In this reaction, when the compound (III) is used in a free acid form orits salt form, the reaction is preferably carried out in the presence ofa conventional condensing agent such as N,N′-dicyclohexylcarbodiimide;N-cyclohexyl-N′-morpholinoethylcarbodiimide;N-cyclohexyl-N′-(4-diethylaminocyclohexyl)carbodiimide;N,N′-diethylcarbodiimide; N,N′-diisopropylcarbodiimide;N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide;N,N-carbonylbis-(2-methylimidazole);pentamethyleneketene-N-cyclohexylimine;diphenylketene-N-cyclohexylimine, ethoxyacetylene;1-alkoxy-2-chloroethylene; trialkyl phosphite; ethyl polyphosphate;isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride);phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkylhaloformate [e.g., ethyl chloroformate, isopropyl chloroformate, etc.];triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt;1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; so-calledVilsmeier reagent prepared by the reaction of N,N-dimethylformamide withthionyl chloride, phosgene, trichloromethyl chloroformate, phosphorousoxychloride, methanesulfonyl chloride, etc.; or the like.

The reaction may also be carried out in the presence of an inorganic ororganic base such as an alkali metal carbonate, alkali metalbicarbonate, tri(lower)alkylamine (e.g., triethylamine,diisopropylethylamine, etc.), pyridine, di(lower)alkylaminopyridine(e.g., 4-dimethylaminopyridine, etc.), N-(lower)alkylmorpholine,N,N-di(lower)alkylbenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to warming.

The compounds obtained by the above Processes 1 to 7 and Process A canbe isolated and purified by a conventional method such as pulverization,recrystallization, column-chromatography, high-performance liquidchromatography (HPLC), reprecipitation, desalting resin columnchromatography, or the like.

The compounds obtained by the above Processes 1 to 2 and Process A maybe obtained as its solvate, such as hydrate, and its solvate, such ashydrate is included within the scope of the present invention.

It is to be noted that each of the object compound (I) may include oneor more stereoisomer such as optical isomer(s) and geometrical isomer(s)due to asymmetric carbon atom(s) and double bond(s) and all such isomersand the mixture thereof are included within the scope of the presentinvention.

The object compound (I) or a salt thereof may include solvated compound[e.g., enclosure compound (e.g., hydrate, etc.)].

The object compound (I) or a salt thereof may include both its crystalform and non-crystal form.

It should be understood that the compounds in the present invention mayinclude the prodrug form.

The patent applications and publications cited herein are incorporatedby reference.

Biological Property of the Polypeptide Compound (I) of the PresentInvention

In order to show the usefulness of the polypeptide compound (I) of thepresent invention, the biological data of the representative compound isexplained in the following.

Test (Antimicrobial Activity):

In vitro antimicrobial activity of the object compound of Example 5disclosed later was determined by MIC_(S) in mouse serum as describedbelow.

Test Method:

The MIC_(S) in mouse serum were determined by the microdilution methodusing ICR mouse serum buffered with 20 mM HEPES buffer (pH 7.3) as atest medium. Inoculum suspension of 10⁶ cells/ml were prepared by ahemocytometric procedure and diluted to obtain an inoculum size ofapproximately 1.0×10³ cells/ml. Microplates were incubated at 37° C. for24 hours in 5% CO₂. The MIC_(S) were defined as the lowestconcentrations at which no visible growth was observed.

Test Result:

MIC (μg/ml) Test compound The object compound Test organism of Example 5Candida albicans FP-633 <0.3From the test result, it is realized that the object compound (I) of thepresent invention has an, antimicrobial activity (especially, antifungalactivity).

In more details, the object compound (I) of the present invention havean antifungal activity, particularly against the following fungi.

Acremonium;

-   Absidia (e.g., Absidia corymbifera, etc);-   Aspergillus (e.g., Aspergillus clavatus, Aspergillus flavus,    Aspergillus fumigatus, Aspergillus nidulans, Aspergillus niger,    Aspergillus terreus, Aspergillus versicolor, etc);-   Blastomyces (e.g., Blastomyces dermatitidis, etc);-   Candida (e.g., Candida albicans, Candida glabrata, Candida    guilliermondii, Candida kefyr, Candida krusei, Candida parapsilosis,    Candida stellatoidea, Candida tropicalis, candida utilis, etc.);-   Cladosporium (e.g., Cladosporium trichloides, etc);-   Coccidioides (e.g., Coccidioides immitis, etc);-   Cryptococcus (e.g., Cryptococcus neoformans, etc);-   Cunninghamella (e.g., Cunninghamella elegans, etc);    Dermatophyte;-   Exophiala (e.g., Exophiala dermatitidis, Exophiala spinifera, etc);-   Epidermophyton (e.g., Epidermophyton floccosum, etc);-   Fonsecaea (e.g., Fonsecaea pedrosoi, etc);-   Fusarium (e.g., Fusarium solani, etc);-   Geotrichum (e.g., Geotrichum candiddum, etc);-   Bistoplasma (e.g., Histoplasma capsulatum var. capsulatum, etc).-   Malassezia (e.g., Malassezia furfur, etc);-   Hicrosporum (e.g., Microsporum canis, Microsporum gypseum, etc);    Mucor;-   Paracoccidioides (e.g., Paracoccidioides brasiliensis, etc);-   Penicillium (e.g., Penicillium marneffei, etc);    Phialophora;-   Pneumocystis (e.g., Pneumocystis carinii, etc);-   Pseudallescheria (e.g., Pseudallescheria boydii, etc);-   Rhizopus (e.g., Rhizopus microsporus var. rhizopodiformis, Rhizopus    oryzae, etc);-   Saccharomyces (e.g., Saccharomyces cerevisiae, etc);    Scopulariopsis;-   Sporothrix (e.g., Sporothrix schenckii, etc);-   Trichophyton (e.g., Trichophyton mentagrophytes, Trichophyton    rubrum, etc)-   Trichosporon (e.g., Trichosporon asahii, Trichosporon cutaneum,    etc).

The above fungi are well-known to cause various infection diseases inskin, hair, nail, oral mucosa, gastrointestinal tract, bronchus, lung,endocardium, brain, meninges, urinary organ, vaginal protion, oralcavity, ophthalmus, systemic, kidney, bronchus, heart, external auditorycanal, bone, nasal cavity, paranasal cavity, spleen, liver, hypodermaltissue, lymph doct, gastrointestine, articulation, muscle, tendon,interstitial plasma cell in lung, and so on.

Therefore, the object compound (I) of the present invention are usefulfor preventing and treating various infectious diseases, such asdermatophytosis (e.g., trichophytosis, etc), pityriasis versicolor,candidiasis, cryptococcosis, geotrichosis, trichosporosis,aspergillosis, penicilliosis, fusariosis, zygomycosis, sporotrichosis,chromomycosis, coccidioidomycosis, histoplasmosis, blastomycosis,paracoccidioidomycosis, pseudallescheriosis, mycetoma, mycotickeratitis, otomycosis, pneumocystosis, and so on.

The pharmaceutical composition of the present invention can be used inthe form of a pharmaceutical preparation, for example, in solid,semisolid or liquid form, which contains the object compound (I) or apharmaceutically acceptable salt thereof, as an active ingredient inadmixture with an organic or inorganic carrier or excipient which issuitable for rectal; pulmonary (nasal or buccal inhalation); ocular;external (topical); oral administration; parenteral (includingsubcutaneous, intravenous and intramuscular) administrations;insufflation (including aerosols from metered dose inhalator);nebulizer; or dry powder inhalator.

The active ingredient may be compounded, for example, with the usualnon-toxic, pharmaceutically acceptable carriers in a solid form such asgranules, tablets, dragees, pellets, troches, capsules, orsuppositories; creams; ointments; aerosols; powders for insufflation; ina liquid form such as solutions, emulsions, or suspensions forinjection; ingestion; eye drops; and any other form suitable for use.And, if necessary, there may be included in the above preparationauxiliary substance such as stabilizing, thickening, wetting,emulsifying and coloring agents; perfumes or buffer; or any othercommonly may be used as additives.

The object compound (I) or a pharmaceutically acceptable salt thereofis/are included in the pharmaceutical composition in an amountsufficient to produce the desired antimicrobial effect upon the processor condition of diseases.

For applying the composition to humans, it is preferable to apply it byintravenous, intramuscular, pulmonary, oral administration, eye dropadministration or insufflation. While the dosage of therapeuticallyeffective amount of the object compound (I) varies from and also dependsupon the age and condition of each individual patient to be treated, inthe case of intravenous administration, a daily dose of 0.01-20 mg ofthe object compound (I) per kg weight of human being in the case ofintramuscular administration, a daily dose of 0.1-20 mg of the objectcompound (I) per kg weight of human being, in case of oraladministration, a daily dose of 0.5-50 mg of the object compound (I) perkg weight of human being is generally given for treating or preventinginfectious diseases.

Especially in case of the treatment of prevention of Pneumocystiscarinii infection, the followings are to be noted.

For administration by inhalation, the compounds of the present invetionare conveniently delivered in the form of an aerosol spray presentationform pressurized as powders which may be formulated and the powdercompositions may be inhaled with the aid of an insufflation powderinhaler device. The preferred delivery system for inhalation is ametered dose inhalation aerosol, which may be formulated as a suspensionor solution of compound in suitable propellants such as fluorocarbons orhydrocarbons.

Because of desirability to directly treat lung and bronchi, aerosoladministration is a preferred method of administration. Insufflation isalso a desirable method, especially where infection may have spread toears and other body cavities.

Alternatively, parenteral administration may be employed using dripintravenous administration.

The following Preparations and Examples are given for the purpose ofillustrating the present invention in more detail.

The Starting Compounds used and the Object Compounds obtained in thefollowing Preparations 1 to 23 are given in the table as below, in whichthe formulas of the starting compounds are in the upper column and theformulas of the object compounds are in the lower column, respectively.

Preparation No. Formula 1

2

3

4

5

6

7

8

9

10

11˜21

Preparation No. R X 11

Na 12

Na 13

Na 14

Na 15

16

17

Na 18

19

Na 20

Na 21

Na

Prepara- tion No. Formula 22

23

PREPARATION 1

A solution of starting compound (20 g) in 1,4-dioxane (100 ml) wastreated with a solution of 1N-sodium hydroxide (44.2 ml) diluted to 100ml with water, and to the stirred mixture was added a solution ofdi-tert-butyldicarbonate (9.2 g) in 1,4-dioxane (50 ml) and then stirredfor 2 hours at room temperature. 500 ml of pH 6.86 phosphate buffer and100 ml ethyl acetate were added and the mixture was stirred and theorganic layer discarded. The aqueous layer was adjusted to pH 7.0 with1N-hydrochloric acid then evaporated to remove organic solvent,filtered, and purified by ODS column chromatography eluting with aqueousmethanol (5-15%). Object compound containing fractions were pooled,evaporated, and lyophilized to give object compound (19.61 g) as anamorphous white powder.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.8 Hz), 1.07 (3H, d, J=5.5 Hz), 1.34(9H, s), 1.40-2.50 (9H, m), 2.80-3.0 (1H, m), 3.4-4.5 (15H, m),4.70-5.40 (8H, m), 6.60-7.05 (6H, m), 7.25-8.00 (5H, m), 8.71 (1H, s).

MASS (m/z): 1003.3 (M⁺−1).

PREPARATION 2

A mixture of starting compound (500 mg), N,N-dimethylformamide (5 ml)and synthetic A-4 zeolite (500 mg, Wako Chemical) was treated withdiisopropyl ethylamine (66 mg), followed by methanesulfonyl chloride(58.5 mg) dropwise. After 1 hour at room temperature, furtherdiisopropyl ethylamine (66 mg) and methanesulfonyl chloride (58.5 mg)were added. After 1.5 hours, additional diisopropylamine (66 mg) andmethanesulfonyl chloride (58.5 mg) were added. After 1.5 hours, themixture was filtered and the filtrate was poured into ethyl acetate. Theprecipitate was collected, washed with ethyl acetate and dried. Thepowder was dissolved in saturated sodium hydrogen carbonate solutionthen purified by ODS column chromatography (Daisogel SP-120 ODS Daiso)eluting with aqueous methanol (5-12.5%). Object compound-containingfractions were pooled, evaporated to remove methanol, and lyophilized togive object compound (210 mg) as an amorphous white powder.

IR (KBr): 2258.2, 1664.3, 1629.6, 1529.3, 1517.7, 1446.4, 1268.9 cm⁻¹.

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6.7 Hz), 1.07 (3H, d, J=5 Hz),1.40-3.00 (9H, m), 3.10-4.50 (15H, m), 4.50-5.30 (10H, m), 5.66-5.69(1H, m), 6.73 (1H, d, J=8.2 Hz), 6.82 (1H, d, J=8 Hz), 7.05 (1H, d,J=1.7 Hz), 7.33 (5H, s), 7.20-7.50 (3H, m), 7.6-7.7 (1H, m), 8.27 (1H,d, J=8.3 Hz), 8.84 (1H, s).

MASS (m/z): 1081.3 (M⁺+Na).

Elemental Analysis Calcd. for C₄₃H₅₅N₈O₂₀SNa.6H₂O: C, 44.25, H, 5.79, N,9.60. Found: C, 44.30, H, 5.79, N, 9.48.

The following compounds [Preparations 3 to 5] were obtained according toa similar manner to that of Preparation 2.

PREPARATION 3

IR (KBr): 2256.3, 1631.5, 1538.9, 1513.8, 1442.5, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.12 (3H, d, J=5.5 Hz),1.20-1.60 (8H, m), 1.65-3.05 (13H, m), 3.21 (3H, s), 3.30 (2H, t, J=6.4Hz), 3.45-4.57 (16H, m), 4.70-5.30 (7H, m), 5.87 (1H, d, J=6.1 Hz), 6.72(1H, d, J=8.2 Hz), 6.76-6.81 (1H, m), 6.98 (1H, d, J=1.3 Hz), 7.13 (2H,d, J=8.8 Hz), 7.40-7.53 (2H, m), 7.79 (1H, br s), 7.98 (2H, d, J=8.7Hz), 8.10 (4H, s), 8.34 (1H, d, J=7.9 Hz), 8.72 (1H, d, J=5.7 Hz), 8.73(1H, s).

MASS (m/z): 1293.4 (M⁺−Na).

Elemental Analysis Calcd. for C₅₈H₇₃N₁₀O₂₀SNa.6H₂O: C, 48.87, H, 6.01,N, 9.83. Found: C, 48.69, H, 6.09, N, 9.70.

PREPARATION 4

IR (KBr): 2256.3, 1666.2, 1631.5, 1535.1, 1515.8, 1448.3, 1442.5,1272.8, 1251.6, 1166.7, 1083.8, 1047.2 cm⁻¹.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.1 Hz), 1.35(9H, s), 1.50-3.00 (9H, m), 3.10-4.50 (17H, m), 4.65-5.00 (5H, m),5.15-5.17 (2H, m), 5.70-5.90 (1H, m), 6.68-6.78 (2H, m), 6.86-6.96 (2H,m), 7.32 (1H, d, J=8 Hz), 7.40-7.50 (1H, m), 7.70-7.80 (1H, m),8.30-8.40 (1H, m), 8.72 (1H, s).

MASS (m/z): 985.3 (M⁺−Na).

Elemental Analysis Calcd. for C₄₀H₅₈N₈O₁₉SNa.9H₂O: C, 41.02, H, 6.45, N,9.57. Found: C, 41.35, H, 6.42, N, 9.61.

PREPARATION 5

IR (KBr): 2256.3, 1668.1, 1648.8, 1631.5, 1538.9, 1513.8, 1454.1, 1267.0cm⁻¹.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.8 Hz), 1.07 (3H, d, J=5.2 Hz),1.5-2.9 (10H, m), 3.2-4.5 (15H, m), 4.7-5.2 (9H, m), 5.7-5.8 (1H, m),6.60-6.78 (2H, m), 6.96 (1H, br s), 7.33 (5H, s), 7.2-7.5 (3H, m),7.7-7.8 (1H, m), 8.3 (1H, d, J=7.5 Hz), 8.73 (1H, br s).

MASS (m/z): 1065.2 (M⁺+Na).

Elemental Analysis Calcd. for C₄₃H₅₅N₈O₁₉SNa.7H₂O: C, 44.18, H, 5.95, N,9.58. Found: C, 44.21, H, 5.82, N, 9.54.

PREPARATION 6

A solution of starting compound (2.0 g) in methanol (100 ml)-water (20ml) was treated with cobalt(II) chloride hexahydrate (1.89 g) and thenstirred to give a pink solution. Sodium borohydride (1.5 g) was thenadded portion wise and then stirred for 1 hour at room temperature. Thereaction mixture was filtered through a bed of celite, washing withmethanol (100 ml)-water (30 ml) solution. The ice-cooled filtrate wasthen treated dropwise with a solution of benzyloxy carbonyl chloride(Z-chloride) (0.34 ml) in tetrahydrofuran (5 ml) and stirred for 1 hourat the same temperature. Ethyl acetate (50 ml) was added followed bywater (200 ml) and after stirring-5 minutes, the separated organic layerwas discarded. The aqueous layer was adjusted to pH 8.8 and evaporatedto remove organic solvent and then purified by ODS columnchromatography, eluting with aqueous acetonitrile (10-30%). Objectcompound containing fractions were pooled, evaporated, and lyophilizedto give object compound (1.61 g) as an amorphous white powder.

IR (KBr): 1666.2, 1631.5, 1517.7, 1444.4, 1267.0 cm⁻¹.

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6.7 Hz), 1.00-1.15 (3H, m), 1.33 (9H,s), 1.35-2.10 (6H, m), 2.10-2.50 (4H, m), 2.80-3.30 (4H, m), 3.60-4.55(12H, m), 4.60-4.90 (2H, m), 4.99 (2H, s), 4.50-5.30 (4H, m), 6.60-7.10(4H, m), 7.33 (5H, s), 7.35-7.90 (3H, m), 8.72 (1H, br s).

MASS (m/z): 1123.3 (M⁺−Na).

Elemental Analysis Calcd. for C₄₈H₆₇N₈O₂₁SNa.6H₂O: C, 45.93, H, 6.34, N,8.93. Found: C, 45.68, H, 6.33, N, 8.82.

PREPARATION 7

A solution of starting compound (2.0 g) in methanol (30 ml) was treatedwith wet 10% palladium on carbon (1.5 g) and exposed to one atmosphereof hydrogen gas via balloon. After 5.5 hours, water (4 ml) was added andhydrogenation continued for a further 30 minutes. Methanol (100 ml) wasadded and the catalyst removed by filtration. The solution wasconcentrated in vacuo to remove methanol and the aqueous residuelyophilized to give object compound (1.69 g) as a pink colored amorphouspowder.

IR (KBr): 2256.3, 1648.8, 1631.5, 1538.9, 1515.8, 1440.6, 1083.8, 1047.2cm⁻¹.

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.9 Hz),1.7-2.8 (10H, m), 3.0-4.5 (19H, m), 4.6-5.3 (6H, m), 5.85-6.0 (1H, m),6.72 (1H, d, J=8.2 Hz), 6.82 (1H, dd, J=1.8 and 8.4 Hz), 7.06 (1H, d,J=1.7 Hz), 7.32 (1H, d, J=8.9 Hz), 7.44 (1H, d, J=9.1 Hz), 7.6-7.8 (2H,m), 7.8-8.0 (1H, br s).

MASS (m/z): 901.2 (M⁺−Na).

Elemental Analysis Calcd. for C₃₅H₄₉N₈O₁₈SNa.6H₂O: C, 40.70, H, 5.95, N,10.85. Found: C, 40.60, H, 5.94, N, 10.71.

The following compound was obtained according to a similar manner tothat of Preparation 7.

PREPARATION 8

IR (KBr): 2256.3, 1648.8, 1631.5, 1538.9, 1513.8, 1267.0, 1083.8, 1047.2cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.08 (3H, d, J=5.9 Hz),1.7-2.1 (5H, m), 2.1-2.9 (7H, m), 3.1-4.6 (16H, m), 4.7-5.4 (6H, m), 6.1(1H, br s), 6.70 (1H, d, J=8.2 Hz), 6.75 (1H, d, J=8.2 Hz), 6.96 (1H, brs), 7.2-7.55 (2H, m), 7.6-7.9 (2H, m).

MASS (m/z): 885.3 (M⁺−Na).

Elemental Analysis Calcd. for C₃₅H₄₉N₈O₁₇SNa.6H₂O: C, 41.34, H, 6.05, N,11.02. Found: C, 41.58, H, 5.99, N, 10.94.

PREPARATION 9

A suspension of starting compound (1.6 g) in dichloromethane (41 ml) wasstirred with cooling at 5° C. and treated with triethylsilane (1.1 ml),followed by trifluoroacetic acid (5.3 ml) dropwise over 30 minutes.After warming to room temperature, the clear solution was stirred for 2hours, then poured into 450 ml of pH 6.86 phosphate buffer and adjustedto pH 8.5 with 4N-sodium hydroxide solution. Organic solvent was removedby evaporation and the remaining aqueous solution purified by ODS columnchromatography, eluting with aqueous acetonitrile (5-20%). Objectcompound-containing fractions were pooled, evaporated, and lyophilizedto give object compound (1.25 g) as an amorphous white powder.

IR (KBr): 1633.4, 1537.0, 1517.7, 1440.6, 1267.0 cm⁻¹.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.7 Hz), 1.12 (3H, d, J=5.8 Hz), 1.27(2H, d, J=6.6 Hz), 1.28-1.70 (2H, m), 1.75-2.45 (4H, m), 2.65-3.30 (5H,m), 3.50-4.50 (11H, m), 4.60-4.90 (2H, m), 5.00 (2H, s), 5.05-5.40 (5H,m), 6.70 (2H, d, J=8.2 Hz), 6.76 (2H, d, J=8.2 Hz), 6.96 (1H, s),7.00-7.15 (1H, m), 7.34 (5H, s), 7.40-7.95 (3H, m), 8.60-8.90 (1H, m).

MASS (m/z): 1023.3 (M⁺−1).

Elemental Analysis Calcd. for C₄₃H₆₀N₈O₁₉S.6H₂O: C, 45.58, H, 6.40, N,9.89. Found: C, 45.49, H, 6.24, N, 9.70.

PREPARATION 10

A solution of starting compound (3 g) in N,N-dimethylformamide (60 ml)was treated with4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,3,4-thiadiazol-2-yl]benzoicacid benzotriazol-1-yl ester (2.65 g) and diisopropylethylamine (0.564ml) and stirred for 4 hours 20 minutes at room temperature. Ethylacetate (1 l) was added and the resulting precipitate collected, washedwith isopropyl ether, and dried to give object compound (5.62 g) as acrude powder, which was used directly in the next step withoutpurification.

The following compounds [Preparations 11 to 17] were obtained accordingto a similar manner to that of Preparation 10.

PREPARATION 11

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 12

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 13

MASS (m/z): 1299.3 (M⁺−Na).

PREPARATION 14

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 15

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 16

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 17

MASS (m/z): 1237.3 (M⁺−Na).

PREPARATION 18

A mixture of4-[2-(4-pentyloxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid (1.44 g), 1-hydroxybenzotriazole (714 mg), diisopropyl ethylamine(0.58 ml) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidehydrochloride (810 mg) in N,N-dimethylformamide (50 ml) was stirred 6hours at room temperature, then treated with starting compound (2 g) andstirred overnight. Additional N,N-dimethylformamide (20 ml) was addedand stirring continued for a further 5.5 hours. The clear solution waspoured into ethyl acetate (1 l) and the precipitate collected and washedwith isopropyl ether and dried to give crude object compound (3.58 g),which was used directly in the next step without purification.

The following compounds [Preparations 19 and 20] were obtained accordingto a similar manner to that of Preparation 18.

PREPARATION 19

MASS (m/z): 1286.3 (M⁺−Na).

PREPARATION 20

MASS (m/z): 1354.4 (M⁺−Na).

The following compound was obtained according to a similar manner tothat of Preparation 18.

PREPARATION 21

IR (KBr): 1648.8, 1631.5, 1537.0, 1513.8, 1456.0 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=7 Hz), 1.10 (3H, d, J=5.6 Hz), 1.18(6H, d, J=6 Hz), 1.4-5.3 (38H, m), 5.88 (1H, d, J=6 Hz), 6.71 (1H, d,J=8 Hz), 6.75-6.80 (1H, m), 6.97 (1H, br s), 7.12 (2H, d, J=9 Hz), 7.42(1H, d, J=7.6 Hz), 7.50 (1H, d, J=9 Hz), 7.78 (2H, d, J=8.8 Hz), 7.7-8.0(1H, br s), 7.96 (4H, s), 8.32 (1H, d, J=8 Hz), 8.50 (1H, d, J=7.1 Hz),8.72 (1H, s), 8.79 (1H, s).

MASS (m/z): 1301.4 (M⁺−Na).

The following compounds [Preparations 22 to 23] were obtained accordingto a similar manner to that of Preparation 10.

PREPARATION 22

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.6 Hz), 6.67 (1H, d, J=6.9 Hz),6.73-6.75 (1H, m), 6.96 (1H, br s), 7.07 (2H, d, J=8.8 Hz), 7.32 (5H,s), 7.73 (2H, d, J=8.7 Hz), 7.87 (2H, d, J=8.5 Hz), 8.06-8.14 (6H, m),8.72 (1H, s), 8.80 (1H, d, J=7.1 Hz).

MASS (m/z): 1465.5 (M⁺−Na).

PREPARATION 23

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 24

To a solution of 1-(tert-butoxycarbonyl)-4-hydroxypiperidine (6 g) inN,N-dimethylformamide (30 ml) was portion wise added sodium hydride(60%, 1.6 g) at 5° C. with stirring. The mixture was stirred at roomtemperature for 0.5 hour and at 60° C. for an hour. To the reactionmixture was added dropwise 1,4-dibromobutane (19 g) at 5° C. withstirring. The mixture was stirred at room temperature for 4 hours and at50° C. for 2 hours. The reaction mixture was poured into ice-water andextracted with a mixture of ethyl acetate and tetrahydrofuran (1:1). Theorganic layer was washed with saturated sodium chloride aqueous solutionand dried over magnesium sulfate. The magnesium sulfate was filteredunder reduced pressure, and the filtrate was concentrated under reducedpressure to give oil. The oil was subjected to column chromatography onsilica gel (silica gel 60 F254, Merck) and eluted with a mixture ofethyl acetate and n-hexane (1:10-1:3). The fractions containing theobjective compound were combined and concentrated under reduced pressureto give 1-(tert-butoxycarbonyl)-4-[(4-bromo)butoxy]piperidine (1.5 g).

NMR (CDCl₃, δ): 1.41 (9H, s), 1.43-1.60 (2H, m), 1.65-1.80 (4H, m),1.85-2.3 (2H, m), 3.02-3.20 (2H, m), 3.38-3.51 (4H, m), 3.68-3.80 (2H,m).

MASS (m/z): 238 (M⁺−Boc−2).

PREPARATION 25

The mixture of 1-(tert-butoxycarbonyl)-4-[4-(bromobutoxy)]piperidine (3g) and 28% sodium methoxide in methanol solution (20 ml) in methanol (50ml) was refluxed for 8.5 hours with stirring. The reaction mixture wasconcentrated under reduced pressure, added water to the residue andadjusted to pH 4 using the hydrochloric acid. The mixture was extractedwith a mixture of ethyl acetate and tetrahydrofuran (1:1), washed withsaturated sodium chloride aqueous solution and dried over magnesiumsulfate. The magnesium sulfate was filtered by suction, and the filtratewas concentrated under reduced pressure to give an oil. The oil wassubjected to column chromatography on silica gel (silica gel 60 F254,Merck) and eluted with a mixture of ethyl acetate and n-hexane(1:5-1:3). The fractions containing the objective compound were combinedand concentrated under reduced pressure to give1-(tert-butoxycarbonyl)-4-(4-methoxybutoxy)piperidine (2.2 g).

NMR (CDCl₃, δ): 1.40 (9H, s), 1.43-1.60 (2H, m), 1.6-1.70.(4H, m),1.76-1.85 (2H, m), 3.01-3.15 (2H, m), 3.33 (3H, s), 3.36-3.50 (5H, m),3.69-3.80 (2H, m).

MASS (m/z): 188 (M⁺−Boc+1).

PREPARATION 26

To a mixture of 1-(tert-butoxycarbonyl)-4-[4-methoxybutoxy]piperidine(2.2 g) and anisole (5 ml) in dichloromethane (10 ml) was added dropwisetrifluoroacetic acid (10 ml) at 5° C. with stirring. The mixture wasstirred at room temperature for 3 hours and evaporated to dryness invacuo at 70° C. to give an oil (2.5 g). The mixture of the above oil(2.5 g), 4-fluorobenzonitrile (1.5 g) and potassium carbonate (3 g) indimethylsulfoxide (25 ml) was heated at 160° C. for 3 hours withstirring. The reaction mixture was poured into ice-water and extractedwith a mixture of ethyl acetate and tetrahydrofuran (1:1). The organiclayer was separated, washed with saturated sodium chloride aqueoussolution and dried over magnesium sulfate. The magnesium sulfate wasfiltered by suction and the filtrate was concentrated under reducedpressure to give solid. The solid was subjected to column chromatographyon silica gel (silica gel 60 F₂₅₄, Merck) and eluted first a mixture ofethyl acetate and n-hexane (1:5), second a mixture of dichloromethaneand methanol (10:1). The fractions containing the objective compoundwere combined and concentrated under reduced pressure to give4-[4-(4-methoxybutoxy)piperidin-1-yl]benzonitrile (2.0 g).

NMR (CDCl₃, δ): 1.58-1.76 (6H, m), 1.89-2.00 (2H, m), 3.08-3.21 (2H, m),3.33 (3H, s), 3.37-3.68 (7H, m), 6.85 (2H, d, J=9 Hz), 7.46 (2H, d, J=9Hz).

MASS (m/z) (API-ES-Positive): 312 (M⁺+Na+1).

PREPARATION 27

The mixture of 4-[4-(4-methoxybutoxy)piperidin-1-yl]benzonitrile (2 g),thiosemicarbazide (1 g) and trifluoroacetic acid (10 ml) in toluene (20ml) was stirred at 60-65° C. for 9 hours. The reaction mixture waspoured into ice-water and adjusted to pH 9 using sodium hydroxideaqueous solution. The mixture was extracted with a mixture of ethylacetate and tetrahydrofuran (1:1), washed with saturated sodium chlorideaqueous solution and dried over magnesium sulfate. The magnesium sulfatewas filtered by suction, the filtrate was concentrated under reducedpressure and the residue was triturated with isopropyl ether. Theprecipitates were collected by filtration, washed with isopropyl etherand dried in vacuo to give2-amino-5-[4-(4-methoxybutoxy)piperidin-1-yl)phenyl][1,3,4]thiadiazole(2.0 g).

NMR (DMSO-d₆, δ): 1.40-1.60 (6H, m), 1.80-2.00 (2H, m), 2.86-3.15 (2H,m), 3.23 (3H, s), 3.30-3.50 (5H, m), 3.50-3.61 (2H, m), 6.98 (2H, d,J=8.9 Hz), 7.19 (2H, s), 7.54 (2H, d, J=8.9 Hz).

MASS (m/z): 363 (M⁺+1).

PREPARATION 28

A mixture of2-amino-5-[4-(4-methoxybutoxy)piperidin-1-yl]phenyl[1,3,4]thiadiazole (2g) and 4-(ethoxycarbonyl)phenacylbromide (2.3 g) in ethanol (25 ml) wasrefluxed for 6 hours with stirring. After cooling, the reaction mixturewas poured into isopropyl ether. The precipitates were collected byfiltration, washed with isopropyl ether and dried in vacuo to givesolid. The mixture of this solid and trifluoroacetic acid (10 ml) inxylene (60 ml) was heated at 130° C. for 6 hours with stirring. Thereaction mixture was concentrated under reduced pressure and the residuewas triturated with isopropyl ether. The precipitates were collected byfiltration, washed with isopropyl ether and dried in vacuo to giveethyl-4-[2-[4-(4-methoxybutoxypiperidin-1-yl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoate(2.4 g).

IR (KBr): 2939, 2854, 1708, 1604, 1469 cm⁻¹.

NMR (DMSO-d₆, δ): 1.34 (3H, t, J=7.2 Hz), 1.40-1.65 (6H, m), 1.75-1.95(4H, m), 3.00-3.20 (2H, m), 3.22 (3H, s), 3.25-3.40 (2H, m), 3.40-3.90(3H, m), 4.33 (2H, q, J=7.5 Hz), 7.02 (2H, d, J=8.8 Hz), 7.57 (2H, d,J=8.8 Hz), 7.75 (2H, d, J=8.8 Hz), 8.00 (1H, s), 8.14 (2H, d, J=9.0 Hz).

MASS (m/z): 535 (M⁺+1).

PREPARATION 29

A solution ofethyl-4-[2-4-[4-methoxybutoxypiperidin-1-yl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoate(2.4 g) and 10% sodium hydroxide aqueous solution (15 ml) in methanol(50 ml) and tetrahydrofuran (25 ml) was refluxed for 6 hours withstirring. The reaction mixture was concentrated under reduced pressure,ice-water was added to the residue and adjusted to pH 3 usinghydrochloric acid. The mixture was shaked with a mixture of ethylacetate and tetrahydrofuran (1:1). The precipitates were collected byfiltration, washed with water and dried in vacuo to give4-[2-[4-(4-methoxybutoxy)piperidin-1-yl-phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid (2 g).

IR (KBr): 2854, 2650, 2550, 1691, 1678, 1608, 1599, 1476 cm⁻¹.

NMR (DMSO-d₆, δ): 1.20-1.60 (6H, m), 1.60-2.05 (2H, m), 3.00-3.30 (2H,m), 3.22 (3H, m), 3.00-4.00 (7H, m), 7.10 (2H, d, J=8.8 Hz), 7.75 (2H,d, J=8.7 Hz), 7.99 (4H, m), 8.81 (1H, s), 12.90 (1H, br s).

MASS (m/z): 507 (M⁺+1).

PREPARATION 30

To a solution of4-[2-[4-(4-methoxybutoxypiperidin-1-yl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid (2.4 g) in dichloromethane (150 ml) was added triethylamine (1.3g), 3-(3-dimethylaminopropyl)-1-ethylcarbodimide hydrochloride (2 g) and1-hydroxybenzotriazole (1 g). The mixture was stirred overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure and the residue was triturated with water. The precipitateswere collected by filtration, washed with water and isopropyl ether anddried in vacuo to give4-[2-[4-(4-methoxybutoxy)piperidin-1-yl-phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid benzotriazol-1-yl ester (2.5 g).

IR (KBr): 3427, 2937, 2856, 1774, 1602, 1471 cm⁻¹.

NMR (DMSO-d₆, δ): 1.30-1.65 (6H, m), 1.70-2.10 (2H, m), 3.21 (3H, m),2.80-3.60 (7H, m), 3.60-3.80 (2H, m), 7.05-8.00 (10H, m), 8.00 (1H, s),8.21 (1H, d, J=8.6 Hz), 8.33 (1H, d, J=8.6 Hz).

MASS (m/z): 624 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 26.

PREPARATION 31 4-(3-Methoxypropoxypiperidin-1-yl)benzonitrile

IR (KBr): 2931, 2866, 2215, 1678, 1604, 1516 cm⁻¹.

NMR (DMSO-d₆, δ): 1.35-1.60 (2H, m), 1.60-1.80 (2H, m), 1.80-2.00 (2H,m), 2.86-3.25 (2H, m), 3.21 (3H, s), 3.30-3.60 (5H, m), 3.60-3.80 (2H,m), 7.01 (2H, d, J=9 Hz), 7.55 (2H, d, J=8.9 Hz).

MASS (m/z): 275 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 27.

PREPARATION 322-Amino-5-[4-(3-methoxypropoxypiperidin-1-yl)phenyl][1,3,4]thiadiazole

NMR (DMSO-d₆, δ): 1.30-1.60 (2H, m), 1.65-1.80 (2H, m), 1.80-2.00 (2H,m), 2.80-3.20 (2H, m), 3.21 (3H, s), 3.30-3.70 (7H, m), 6.98 (2H, d,J=8.9 Hz), 7.19 (2H, br s), 7.54 (2H, d, J=8.8 Hz).

MASS (m/z): 349 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 28.

PREPARATION 33Ethyl-4-[2-[4-(3-methoxypropoxypiperidin-1-yl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoate

IR (KBr): 3411, 3211, 3132, 2943, 2862, 1709, 1604 cm⁻¹.

NMR (DMSO-d₆, δ): 1.30-1.60 (5H, m), 1.65-1.80 (2H, m), 1.80-2.00 (2H,m), 2.80-3.10 (2H, m), 3.22 (3H, s), 3.30-3.80 (6H, m), 4.20-4.50 (3H,m), 6.98 (2H, d, J=9 Hz), 7.40 (1H, 8), 7.54 (2H, d, J=8.8 Hz),7.80-8.40 (4H, m).

MASS (m/z): 521 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 29.

PREPARATION 344-[2-[4-(3-Methoxypropoxypiperidin-1-yl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid

IR (KBr): 3423, 2935, 2858, 2650, 2550, 1682, 1603, 1468 cm⁻¹.

NMR (DMSO-d₆, δ): 1.40-1.60 (2H, m), 1.60-1.80 (2H, m), 1.80-2.00 (2H,m), 2.80-3.20 (2H, m), 3.22 (3H, s), 3.30-3.80 (7H, m), 6.98 (2H, d,J=8.7 Hz), 7.19 (1H, s), 7.54 (2H, d, J=8.7 Hz), 7.80-8.20 (4H, m).

MASS (m/z): 493 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 30.

PREPARATION 354-[2-[4-(3-Methoxypropoxypiperidin-1-yl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 3464, 3429, 3425, 3402, 2932, 2931, 1774, 1605, 1469 cm⁻¹.

NMR (DMSO-d₆, δ): 1.30-1.60 (2H, m), 1.60-1.80 (2H, m), 1.80-2.00 (2H,m), 2.80-3.30 (2H, m), 3.22 (3H, s), 3.35-3.80 (7H, m), 7.08 (2H, d,J=9.1 Hz), 7.20-8.00 (8H, m), 8.00 (1H, s), 8.14 (1H, d, J=8.6 Hz), 8.33(1H, d, J=8.5 Hz).

MASS (m/z): 610 (M⁺+1).

PREPARATION 36

A mixture of methyl 4-methylsulfinylbenzoate (6.0 g), sodium acetate (11g) and acetic anhydride (60 ml) was stirred for 7.5 hours at 180° C. Thereaction mixture was cooled and filtered by suction. The filtrate wasconcentrated under reduced pressure and the residue was triturated withwater. The precipitates were collected by filtration, washed withaqueous sodium carbonate and water. The solid was subjected to columnchromatography on silica gel (silica gel 60 F254, Merck: 200 g) andeluted with a mixture of ethyl acetate and toluene (1:5). The fractionscontaining the objective compound were combined and concentrated underreduced pressure to give methyl 4-acetoxymethylthiobenzoate (5.5 g).

IR (KBr): 1746, 1704, 1593 cm⁻¹.

NMR (CDCl₃, δ): 2.12 (3H, s), 3.92 (3H, s), 5.50 (2H, s), 7.63 (2H, d,J=8.3 Hz), 7.98 (2H, d, J=8,3 Hz).

MASS (m/z) (API-ES-Positive): 263 (M⁺+23).

PREPARATION 37

To a solution of methyl 4-acetoxymethylthiobenzoate (15.5 g) in amixture of methanol (20 ml) and dichloromethane (60 ml) was portionwiseadded magnesium monoperoxyphthalate hexahydrate (24 g) at 5° C., withstirring. The mixture was stirred at room temperature for 2 hours. Thereaction mixture was washed with ice-water, aqueous sodium carbonate andbrine, then dried over magnesium sulfate. The organic solvent wasconcentrated under reduced pressure to giveacetoxymethyl-(4-methoxycarbonylphenyl)sulfone (5.9 g).

IR (KBr): 1759, 1724, 1434 cm⁻¹.

NMR (CDCl₃, δ): 2.09 (3H, s), 3.98 (3H, s), 5.18 (2H, s), 8.01 (2H, d,J=8.5 Hz), 8.26 (2H, d, J=8.5 Hz).

MASS (m/z): 273 (M⁺+1).

PREPARATION 38

To a solution of methyl 4-acetoxymethylsulfonylbenzoate (5.5 g) in amixture of tetrahydrofuran (50 ml) and methanol (25 ml) was addeddropwise 10% aqueous sodium hydroxide at 5° C. with stirring. Themixture was stirred at room temperature for 3 hours. The reactionmixture was concentrated under reduced pressure and to the residue wasadded water. The solution was washed with toluene and the aqueous layerwas concentrated under reduced pressure and dried in vacuo at 50° C. togive sodium methoxycarbonylbenzenesulfinate (4.5 g).

IR (KBr): 3424, 3300, 1718, 1594 cm⁻¹.

NMR (DMSO-d₆, δ): 3.84 (3H, s), 7.60 (2H, d, J=8.0 Hz), 7.92 (2H, d,J=8.0 Hz).

MASS (m/z) (API-ES-Positive): 245 (M⁺+23).

PREPARATION 39

A mixture of sodium-4-(1-methoxycarbonyl)benzene sulfinate (2.2 g) and1,7-dibromoheptane (2.6 g) in N,N-dimethylformamide (50 ml) was stirredat 100° C. for 5 hours. The reaction mixture was concentrated underreduced pressure and the residue was triturated with water. The mixturewas extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1),washed with brine and dried over magnesium sulfate. After removing themagnesium sulfate, the filtrate was concentrated under reduced pressureto give a yellow oil. The oily product was subjected to columnchromatography on silica gel (silica gel 60 F254, Merck: 250 g) andeluted with a mixture of ethyl acetate and toluene (1:10). The fractionscontaining the objective compound were combined and concentrated underreduced pressure to give7-bromoheptyl-[4-(methoxycarbonyl)phenyl]sulfone (1.4 g).

IR (Neat): 3423, 2927, 2852, 1725, 1280 cm⁻¹.

NMR (CDCl₃, δ): 1.20-1.43 (6H, m), 1.60-1.85 (4H, m), 3.11 (2H, m), 3.38(2H, t, J=6.7 Hz), 3.98 (3H, s), 8.00 (2H, d, J=8.4 Hz), 8.23 (2H, d,J=8.4 Hz).

MASS (m/z): 379 (M⁺).

PREPARATION 40

A mixture of 7-bromoheptyl-[(4-methoxycarbonyl)phenyl]sulfone (1.4 g)and sodium methoxide in methanol solution (28%) (2 ml) in methanol(20ml) was refluxed for 10 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and subjected to columnchromatography on silica gel (silica gel 60 F254, Merck) and eluted witha mixture of ethyl acetate and toluene (1:5-1:3). The fractionscontaining the objective compound were combined and concentrated underreduced pressure to give7-methoxyheptyl[4-(methoxycarbonyl)phenyl]sulfone (0.85 g).

IR (Neat): 2929, 2857, 1723, 1280 cm⁻¹.

NMR (CDCl₃, δ): 3.15-3.40 (8H, m), 3.40-3.80 (4H, m), 3.98 (3H, s), 8.00(2H, d, J=8.5 Hz), 8.23 (2H, d, J=8.5 Hz).

MASS (m/z): 328 (M⁺+1).

PREPARATION 41

A mixture of 7-methoxyheptyl-[4-(methoxycarbonyl)phenyl]sulfone (0.85 g)and 1N-aqueous sodium hydroxide (5 ml) in a mixture of ethanol (20 ml)and tetrahydrofuran (10 ml) was stirred at 80° C. for 5 hours. Thereaction mixture was concentrated under reduced pressure and the residuewas triturated with water. The solution was adjusted to pH 1.0 usingdiluted hydrochloric acid. The precipitates were collected byfiltration, washed with water and dried in vacuo to give7-methoxyheptyl-(4-carboxyphenyl)sulfone (0.8 g) white solid.

IR (KBr): 2674, 2555, 1698, 1425, 1285 cm⁻¹.

NMR (DMSO-d₆, δ): 1.1-1.4 (6H, m), 1.40-1.60 (4H, m), 3.21 (3H, s),3.18-3.40 (4H, m), 8.00 (2H, d, J=8.5 Hz), 8.18 (2H, d, J=8.5 Hz).

MASS (m/z): 315 (M⁺+1).

PREPARATION 42

A mixture of 7-methoxyheptyl-4-carboxyphenylsulfone (0.8 g) and thionylchloride (10 ml) was refluxed for 2 hours with stirring. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (10 ml). To a mixture of4-(methoxycarbonyl)benzamide oxime (0.49 g) in pyridine (25 ml) wasadded dropwise the above acid chloride solution at 5° C. with stirring.The mixture was stirred at 5° C. for 0.5 hour and continued at roomtemperature for an hour. The reaction mixture was concentrated underreduced pressure and the residue was triturated with water. Theprecipitates were collected by filtration, washed with water and driedto give4-(methoxycarbonyl)-O-4′-[(7-methoxyheptylsulfonyl)benzoyl]benzamideoxime (1.0 g).

IR (KBr): 3492, 3369, 2933, 2857, 1724, 1616, 1276 cm⁻¹.

NMR (DMSO-d₆, δ): 1.15-1.54 (12H, m), 3.23 (3H, s), 3.22-3.40 (2H, m),3.90 (3H, s), 7.25 (2H, br s), 7.95 (2H, d, J=8.3 Hz), 8.00-8.17 (4H,m), 8.47 (2H, d, J=8.3 Hz).

MASS (m/z): 491 (M⁺+1).

PREPARATION 43

A solution of4-methoxycarbonyl-O-[4′-(7-methoxyheptylsulfonyl)benzoyl]benzamide oxime(1.0 g) in N,N-dimethylformamide (10 ml) was stirred at 100° C. for 6hours. The reaction mixture was poured into ice-water and adjusted to pH1 using diluted hydrochloric acid. The precipitates were collected byfiltration, washed with water and dried to givemethyl-4-[5-[4-(7-methoxyheptylsulfonyl)phenyl]-1,2,4-oxadiazol-3-yl]benzoate(0.82 g).

IR (KBr): 2931, 2857, 1724, 1280 cm⁻¹.

NMR (DMSO-d₆, δ): 1.20-1.60 (1H, m), 3.17 (3H, s), 3.22-3.43 (4H, m),3.92 (3H, s), 8.17-8.30 (6H, m), 8.47 (2H, d, J=8.3 Hz).

MASS (m/z): 473 (M⁺+1).

PREPARATION 44

A mixture of methyl4-[5-[4-(7-methoxyheptylsulfonyl)phenyl]-1,2,4-oxazol-3-yl]benzoate (0.8g) and 10% sodium hydroxide aqueous solution (2 ml) in a mixture ofethanol (25 ml) and tetrahydrofuran (10 ml) was refluxed for 3.5 hourswith stirring. The reaction mixture was concentrated under reducedpressure and to the residue was added water and adjusted to pH 1 usingdiluted hydrochloric acid. The precipitates were collected byfiltration, washed with water and dried to give4-[5-[4-(7-methoxyheptylsulfonyl)phenyl]-1,2,4-oxadiazol-3-yl]benzoicacid (0.8 g).

IR (KBr): 2931, 2857, 2750, 2650, 1693, 1415 cm⁻¹.

NMR (DMSO-d₆, δ): 1.15-1.60 (10H, m), 3.18 (3H, s), 3.20-3.50 (4H, m),8.16-8.30 (6H, m), 8.47 (2H, d, J=8.4 Hz).

MASS (m/z): 459 (M⁺+1).

PREPARATION 45

To a solution of4-[5-[4-(7-methoxyheptylsulfonyl)phenyl]-1,2,4-oxazol-3-yl]benzoic acid(0.8 g) and triethylamine (0.4 g) in dichloromethane (30 ml) was added3-(3-dimethylaminopropyl)-1-ethylcarbodimide (0.7 g) and1-hydroxybenzotriazole (0.36 g). The mixture was stirred at roomtemperature for 8 hours. The reaction mixture was washed with water,saturated sodium chloride aqueous solution and dried over magnesiumsulfate. After magnesium sulfate was filtered off, the filtrate wasconcentrated under reduced pressure and the residue was triturated withisopropyl ether. The precipitates were collected by filtration, washedwith isopropyl ether and dried in vacuo to give4-[5-[4-(7-methoxyheptylsulfonyl)phenyl]-1,2,4-oxadiazol-3-yl]benzoicacid benzotriazol-1-yl ester (0.89 g).

IR (KBr): 2931, 2857, 1787, 1616, 1409, 1282 cm⁻¹.

NMR (DMSO-d₆, δ): 1.10-1.50 (10H, m), 3.18 (3H, s), 3.22-3.40 (4H, m),7.25-7.60 (2H, m), 7.70 (1H, d, J=8.5 Hz), 7.96 (1H, d, J=8.5 Hz),8.19-8.24 (6H, m), 8.47 (2H, d, J=8.3 Hz).

MASS (m/z): 576 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 39.

PREPARATION 46 1-[4-(Methoxycarbonyl)phenylsulfonyl]-9-bromoheptane

IR (KBr): 2925, 2850, 1724, 1461, 1280 cm⁻¹.

NMR (DMSO-d₆, δ): 1.10-1.35 (10H, m), 1.40-1.55 (2H, m), 1.60-1.80 (2H,m), 3.33-3.41 (2H, m), 3.50 (2H, t, J=6.7 Hz), 3.91 (3H, s), 8.05 (2H,d, J=8.4 Hz), 8.20 (2H, d, J=8.4 Hz).

MASS (m/z): 405 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 40.

PREPARATION 47 1-[4-(Methoxycarbonyl)phenyl]sulfonyl-9-methoxyheptane

IR (KBr): 2927, 2854, 1699, 1425, 1286 cm⁻¹.

NMR (DMSO-d₆, δ): 1.10-1.30 (10H, m), 1.30-1.48 (6H, m), 3.19 (3H, s),3.23-3.39 (4H, m), 3.90 (3H, s), 8.01 (2H, d, J=8.3 Hz), 8.17 (2H, d,J=8.3 Hz).

MASS (m/z): 357 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 41.

PREPARATION 48 1-[4-Carboxyphenylsulfonyl)-9-methoxyheptane

IR (KBr): 2937, 2852, 2672, 2550, 1698, 1425, 1320, 1286 cm⁻¹.

NMR (DMSO-d₆, δ): 1.10-1.30 (10H, m), 1.40-1.47 (4H, m), 3.19 (3H, s),3.23-3.39 (3H, m), 8.01 (2H, d, J=8.3 Hz), 8.17 (2H, d, J=8.3 Hz).

MASS (m/z): 343 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparations 42 and 43.

PREPARATION 49 Methyl4-[5-[4-(9-methoxy-n-nonylsulfonyl)phenyl]-1,2,4-oxadiazol-3-yl]benzoate

IR (KBr): 2925, 2854, 1724, 1612, 1409, 1278 cm⁻¹.

NMR (DMSO-d₆, δ): 1.19-1.57 (14H, m), 3.17 (3H, s), 3.12-3.43 (4H, m),3.92 (3H, s), 8.17-8.30 (6H, m), 8.47 (2H, d, J=8.4 Hz).

MASS (m/z): 501 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 44.

PREPARATION 504-[5-[4′-(9-Methoxy-n-nonylsulfonyl)phenyl]-1,2,4-oxadiazol-3-yl]benzoicacid

IR (KBr): 2927, 2854, 2667, 2550, 1691, 1614, 1415, 1282 cm⁻¹.

NMR (DMSO-d₆, δ): 1.10-1.30 (10H, m), 1.30-1.60 (4H, m), 3.17 (3H, s),3.19-3.46 (4H, m), 8.00-8.27 (6H, m), 8.47 (2H, d, J=8.3 Hz), 13.34 (1H,br s).

MASS (m/z): 487 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 45.

PREPARATION 514-[5-[4-(9-Methoxy-n-nonylsulfonyl)phenyl]-1,2,4-oxadiazol-3-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 2927, 2854, 1785, 1614, 1411, 1282 cm⁻¹.

NMR (DMSO-d₆, δ): 1.10-1.30 (10H, m), 1.30-1.60 (4H, m), 3.17 (3H, s),3.03-3.43 (4H, m), 7.36-7.58 (2H, m), 7.72 (1H, d, J=8.3 Hz), 7.98 (1H,d, J=8.3 Hz), 8.17-8.27 (6H, m), 8.47 (2H, d, J=8.4 Hz).

MASS (m/z): 604 (M⁺+1).

PREPARATION 52

To a mixture of methyl 4-hydroxybenzoate (1.52 g) and potassiumcarbonate (0.76 g) in acetone (30 ml) was added dropwise a solution of1,7-dibromoheptane (3.1 g) in acetone (10 ml) at room temperature withstirring. The mixture was stirred at room temperature for 2.5 hours, andthen refluxed for overnight with stirring. The reaction mixture wasfiltered under reduced pressure and the filtrate was concentrated underreduced pressure to give an oily solid. The oily solid was subjected tocolumn chromatography on silica gel (silica gel 60 F254, Merck: 200 g)and eluted with a mixture of ethyl acetate and n-hexane (1:3). Thefractions containing the objective compound were combined andconcentrated under reduced pressure to give methyl4-(7-bromo-n-heptyloxy]benzoate (2.3 g).

NMR (CDCl₃, δ): 1.43-1.60 (6H, m), 1.74-1.90 (4H, m), 3.42 (2H, t, J=6.8Hz), 3.88 (3H, s), 4.00 (2H, t, J=6.8 Hz), 6.89 (2H, d, J=8.9 Hz), 7.98(2H, d, J=8.9 Hz).

MASS (m/z) (API-ES-Positive): 329 (M⁺).

PREPARATION 53

A solution of methyl 4-[7-bromo-n-heptyloxy)benzoate (2.3 g) in methanol(50 ml) and a solution of 28% sodium methoxide in methanol (3.5 ml) wasrefluxed for 12 hours with stirring. The reaction mixture wasconcentrated under reduced pressure and water was added to the residueand adjusted to pH 1 using hydrochloric acid. The precipitates werecollected by filtration, washed with water and dried in vacuo to give anoil. The oil was subjected to column chromatography on silica gel(silica gel 60 F254, Merck: 100 g) and eluted with a mixture of ethylacetate and n-hexane (1:5). The fractions containing the objectivecompound were combined and concentrated under reduced pressure to givemethyl 4-(7-methoxyheptyloxy)benzoate (1.6 g) as an oil.

IR (Neat): 2937, 2867, 1718, 1607, 1469, 1442 cm⁻¹.

NMR (CDCl₃, δ): 1.15-1.60 (8H, m), 1.60-1.84 (2H, m), 3.33 (3H, s),3.30-3.40 (2H, t, J=6.4 Hz), 3.88 (3H, 9), 4.00 (2H, t, J=6.4 Hz), 6.92(2H, d, J=8.8 Hz), 8.00 (2H, d, J=8.8 Hz).

MASS (m/z): 281 (M⁺+1).

PREPARATION 54

A mixture of methyl 4-(7-methoxy-n-heptyloxy)benzoate (1.5 g) and1N-sodium hydroxide aqueous solution in ethanol (10 ml) andtetrahydrofuran (10 ml) was heated at 40-60° C. for 5 hours withstirring. The reaction mixture was concentrated under reduced pressureand water added to the residue and adjusted to pH 1 using hydrochloricacid. The precipitates were collected by filtration, washed with waterand dried in vacuo to give 4-[7-methoxy-n-heptyloxy)benzoic acid (1.4 g)as a white solid.

IR (KBr): 2937, 2857, 2665, 2561, 1691, 1666, 1606, 1428 cm⁻¹.

NMR (DMSO-d₆, δ): 1.20-1.55 (8H, m), 1.60-1.80 (2H, m), 3.20 (3H, s),3.29 (2H, d, J=6.4 Hz), 4.03 (2H, d, J=6.4 Hz), 7.00 (2H, d, J=8.7 Hz),7.87 (2H, d, J=8.7 Hz).

MASS (m/z) (API-ES-Positive): 289 (M⁺+23), 249.

PREPARATION 55

A mixture of 4-(7-methoxy-n-heptyloxy)benzoic acid (4 g) and thionylchloride (40 ml) was refluxed for 2 hours with stirring. The reactionmixture was concentrated under reduced pressure and the residue wasdissolved in tetrahydrofuran (40 ml). To a mixture of4-(methoxycarbonyl)benzamide oxime (2.8 g) in pyridine (30 ml) was addeddropwise the above acid chloride solution at 5° C. with stirring. Themixture was stirred at 5° C. for 0.5 hour and continued at roomtemperature for 0.5 hour. The reaction mixture was poured into water.The precipitates were collected by filtration, washed with water anddried in vacuo to give4-(methoxycarbonyl)-O-[4-(7-methoxy-n-heptyloxy)benzoyl]benzamide oxime(6.0 g).

IR (KBr): 3478, 3372, 2931, 2854, 1714, 1605 cm⁻¹.

NMR (DMSO-d₆, δ): 1.20-1.55 (8H, m), 1.60-1.80 (2H, m), 3.21 (3H, s),3.30 (3H, t, J=6.4 Hz), 3.89 (3H, s), 4.07 (2H, t, J=6.4 Hz), 7.03 (2H,d, J=8.4 Hz), 7.08 (2H, br s), 7.92 (2H, d, J=8.4 Hz), 8.05 (2H, d,J=8.4 Hz), 8.14 (2H, d, J=8.8 Hz).

MASS (m/z): 443 (M⁺+1).

PREPARATION 56

A solution of4-(methoxycarbonyl)-O-[4-(7-methoxy-n-heptyloxy)benzoyl]benzamide oxime(6.0 g) in N,N-dimethylformamide (60 ml) was stirred at 100° C. for 24hours. The reaction mixture was concentrated under reduced pressure andwater added to the residue and adjusted to pH 1 using hydrochloric acid.The precipitates were collected by filtration, washed with water anddried in vacuo to give a solid. The solid was subjected to columnchromatography on silica gel (silica gel 60 P254, Merck: 300 g) andeluted with a mixture of ethyl acetate and toluene (1:10-1:5). Thefractions containing the objective compound were combined andconcentrated under reduced pressure to give methyl4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoate(5.4 g).

IR (KBr): 2939, 2863, 1722, 1612, 1471, 1417, 1270 cm⁻¹.

NMR (DMSO-d₆, δ): 1.15-1.60 (8H, m), 1.60-1.80 (2H, m), 2.10-2.20 (2H,m), 3.21 (3H, s), 3.90 (3H, s), 4.10 (2H, t, J=6.3 Hz), 7.20 (2H, d,J=8.5 Hz), 8.12-8.27 (6H, m).

MASS (m/z): 425 (M⁺+1).

PREPARATION 57

A mixture of methyl4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoate(5.4 g) and 10% sodium hydroxide aqueous solution (15 ml) in ethanol (60ml) and tetrahydrofuran (30 ml) was stirred at 60-70° C. for 2 hours.The reaction mixture was concentrated under reduced pressure and wateradded to the residue and adjusted to pH 1 using hydrochloric acid. Theprecipitates were collected by filtration, washed with water and driedin vacuo to give4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid(4.4 g).

IR (KBr): 2931, 2857, 2667, 2560, 1693, 1614, 1419 cm⁻¹.

NMR (DMSO-d₆, δ): 1.10-1.50 (8H, m), 1.60-1.80 (2H, m), 3.21 (3H, s),4.10 (2H, t, J=6.3 Hz), 7.18 (2H, d, J=9.1 Hz), 7.90-8.10 (4H, m), 8.13(2H, d, J=8.9 Hz).

MASS (m/z): 411 (M⁺+1).

PREPARATION 58

To a mixture of4-[5-[4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid(2.0 g) and triethylamine (1.1 g) in dichloromethane (60 ml) was added3-(3-dimethylaminopropyl)-1-ethylcarbodimide hydrochloride (1.4 g) and1-hydroxybenzotriazole (0.8 g). The mixture was stirred at roomtemperature overnight. The reaction mixture was washed with water, brineand dried over magnesium sulfate. The magnesium sulfate was filteredoff, and the filtrate was concentrated under reduced pressure, and theresidue was triturated with isopropyl ether. The precipitates werecollected by filtration, washed with isopropyl ether and dried to give4-[5-(4-(7-methoxy-n-heptyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acidbenzotriazol-1-yl ester (2.1 g).

IR (KBr): 2933, 2859, 1781, 1612 cm⁻¹.

NMR (CDCl₃, δ): 1.30-1.70 (8H, m), 1.65-1.90 (2H, m), 3.24 (3H, s), 3.39(2H, t, J=6.4 Hz), 4.06 (2H, t, J=6.4 Hz), 7.05 (2H, d, J=8.9 Hz),7.40-7.65 (3H, m), 8.10-8.25 (3H, m), 8.42 (4H, s).

MASS (m/z): 528 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 52.

PREPARATION 59 Methyl 4-(9-bromo-n-nonyloxy)benzoate

IR (KBr): 2940, 2923, 2856, 1711, 1604, 1511 cm⁻¹.

NMR (CDCl₃, δ): 1.20-1.50 (10H, m), 1.60-1.90 (4H, m), 3.41 (2H, t,J=6.8 Hz), 3.88 (3H, s), 4.00 (2H, t, J=6.8 Hz), 6.91 (2H, d, J=8.8 Hz),7.98 (2H, d, J=8.7 Hz).

MASS (m/z): 357 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 53.

PREPARATION 60 Methyl 4-(9-methoxy-n-nonyloxy)benzoate

IR (KBr): 2929, 2852, 1724, 1606 cm⁻¹.

NMR (CDCl₃, δ): 1.20-1.40 (10H, m), 1.45-1.60 (2H, m), 1.65-1.83 (2H,m), 3.33 (3H, s), 3.37 (2H, t, J=6.5 Hz), 3.88 (3H, s), 4.01 (2H, t,J=6.5 Hz), 6.90 (2H, d, J=8.9 Hz), 8.00 (2H, d, J=8.9 Hz).

MASS (m/z): 308 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 54.

PREPARATION 61 4-(9-Methoxy-n-nonyloxy)benzoic acid

IR (KBr): 2929, 2856, 2650, 2560, 1695, 1664, 1610 cm⁻¹.

NMR (DMSO-d₆, δ): 1.20-1.35 (10H, m), 1.40-1.60 (2H, m), 1.60-1.80 (2H,m), 3.20 (3H, s), 3.28 (2H, t, J=6.4 Hz), 4.02 (2H, t, J=6.4 Hz), 7.00(2H, d, J=8.7 Hz), 7.87 (2H, d, J=8.7 Hz).

The following compound was obtained according to a similar manner tothat of Preparation 55.

PREPARATION 624-(Methoxycarbonyl)-O-4′-(9-methoxy-n-nonyloxy)benzoylbenzamide oxime

IR (KBr): 3488, 3367, 2929, 2856, 1719, 1615, 1589 cm⁻¹.

NMR (DMSO-d₆, δ): 1.20-1.40 (10H, m), 1.40-1.60 (2H, m), 1.60-1.80 (2H,m), 3.20 (3H, s), 3.28 (2H, t, J=6.5 Hz), 3.89 (3H, s), 4.00 (2H, t,J=6.4 Hz), 7.03 (2H, d, J=8.9 Hz), 7.07 (2H, br s), 7.92 (2H, d, J=8.4Hz), 8.05 (2H, d, J=8.4 Hz), 8.14 (2H, d, J=8.9 Hz).

MASS (m/z): 471 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 56.

PREPARATION 63 Methyl4-[5-[4-(9-methoxy-n-nonyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoate

IR (KBr): 2933, 2856, 1722, 1616, 1276 cm⁻¹.

NMR (DMSO-d₆, δ): 1.20-1.40 (10H, m), 1.40-1.60 (2H, m), 1.60-1.80 (2H,m), 3.27-3.33 (2H, m), 3.20 (3H, s), 4.00 (3H, s), 4.05-4.11 (2H, m),7.19 (2H, d, J=9 Hz), 7.90 (2H, d, J=9 Hz), 8.12-8.25 (4H, m).

MASS (m/z): 453 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 57.

PREPARATION 644-[5-[4-(9-Methoxy-n-nonyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acid

IR (KBr): 2931, 2857, 2667, 2560, 1693, 1614, 1419 cm⁻¹.

NMR (DMSO-d₆, δ): 1.15-1.40 (10H, m), 1.40-1.50 (2H, m), 1.60-1.80 (2H,m), 3.21 (3H, s), 3.27 (2H, t, J=6.5 Hz), 4.10 (2H, t, J=6.5 Hz), 7.18(2H, d, J=8.8 Hz), 8.10-8.25 (6H, m).

MASS (m/z): 439 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 58.

PREPARATION 654-[5-[4-(9-Methoxy-n-nonyloxy)phenyl]-1,2,4-oxadiazol-3-yl]benzoic acidbenzotriazol-1-yl ester

IR (KBr): 2931, 2856, 1781, 1612 cm⁻¹.

NMR (CDCl₃, δ): 1.20-1.40 (10H, m), 1.40-1.60 (2H, m), 1.60-1.80 (2H,m), 3.33 (3H, s), 3.37 (2H, t, J=6.5 Hz), 4.06 (2H, t, J=6.5 Hz), 7.05(2H, d, J=8.8 Hz), 7.40-7.60 (3H, m), 8.10-8.20 (3H, m), 8.42 (4H, brs).

MASS (m/z): 556 (M⁺+1).

PREPARATION 66

A mixture of 4-bromophenol (10 g), 1,6-dibromohexane (49.4 g) andpotassium carbonate (9.59 g) in N,N-dimethylformamide (50 ml) wasstirred for 4 hours at 60° C. (bath temp.), and then cooled to ambienttemperature. To the reaction mixture was added ethyl acetate (200 ml),and the mixture was washed with water (200 ml×2) and brine. The organiclayer was dried over magnesium sulfate. Magnesium sulfate was filteredoff, and the filtrate was evaporated under reduced pressure to give acrude product. The crude product was purified by silica gelchromatography (1:0-1:1 hexane-ethyl acetate) to give1-bromo-4-(6-bromohexyloxy)benzene (15.61 g).

IR (KBr): 2940.9, 2910.1, 2861.8, 1490.7, 1467.6, 1292.1, 1245.8 cm⁻¹.

NMR (DMSO-d₆, δ): 1.3-1.5 (4H, m), 1.6-2.0 (4H, m), 3.54 (2H, t, J=6.6Hz), 3.94 (2H, t, J=6.4 Hz), 6.90 (2H, d, J=4.5 Hz), 7.43 (2H, d, J=4.5Hz).

PREPARATION 67

A mixture of 1-bromo-4-(6-bromohexyloxy)benzene (6.0 g) and sodiummethylate (28% in methanol) (10.3 ml) in methanol (30 ml) was stirredfor 2 hours at 70° C. (bath temp.), and then the solvent was evaporated.The residue was neutralized by 1N-hydrochloric acid and extracted withethyl acetate (100 ml), and washed with water and brine. The organiclayer was dried over magnesium sulfate. Magnesium sulfate was filteredoff, and the filtrate was evaporated under reduced pressure to give acrude product. The crude product was purified by silica gelchromatography (20:1-10:1 hexane-ethyl acetate) to give1-bromo-4-(6-methoxyhexyloxy)benzene (15.61 g) as a colorless oil.

IR (KBr): 2937.1, 2861.8, 1591.0, 1488.8, 1473.3, 1286.3, 1243.9, 823.5cm⁻¹.

NMR (DMSO-d₆, δ): 1.2-1.6 (6H, m), 1.6-1.8 (2H, m), 3.21 (3H, s), 3.30(2H, t, J=6.4 Hz), 3.93 (2H, t, J=6.4 Hz), 6.90 (2H, d, J=6.8 Hz), 7.42(2H, d, J=6.8 Hz).

PREPARATION 68

Under a nitrogen atmosphere, to a mixture of1-bromo-4-(6-methoxyhexyloxy)benzene (3.68 g), 2-methyl-3-butyn-2-ol(1.86 ml) and triethylamine (18 ml) in pyridine (7.4 ml) was addedtriphenylphosphine (67.2 mg), copper(I) iodide (24.4 mg) anddichlorobis(triphenylphosphine)palladium(II) (18.0 mg), and refluxedovernight. After cooling, insoluble material was filtered off and washedwith isopropyl ether. The filtrate was evaporated under reducedpressure. To the residue was added isopropyl ether and the mixture waswashed with 0.1N-hydrochloric acid, water and brine. The organic layerwas dried over magnesium sulfate. Magnesium sulfate was filtered off,and the filtrate was evaporated under reduced pressure to give a crudeyellow oil. The crude yellow oil was purified by silica gelchromatography (10:1-2:1 hexane-ethyl acetate) to give4-[4-(6-methoxyhexyloxy)phenyl]-2-methyl-3-butyn-2-ol (3.17 g) as ayellow powder.

IR (KBr): 3426.9, 3415.3, 2979.5, 2937.1, 2858.0, 2219.7, 1606.4,1510.0, 1243.9, 1168.7, 1105.0 cm⁻¹.

NMR (DMSO-d₆, δ): 1.2-1.6 (12H, m), 1.6-1.8 (2H, m), 3.20 (3H, s), 3.30(2H, t, J=6.4 Hz), 3.95 (2H, t, J=6.4 Hz), 5.39 (1H, s), 6.89 (2H, d,J=8.7 Hz), 7.29 (2H, d, J=8.7 Hz).

PREPARATION 69

Under a nitrogen atmosphere, to a solution of4-[4-(6-methoxyhexyloxy)phenyl]-2-methyl-3-butyn-2-ol (3.0 g) in toluene(18 ml) was added sodium hydride (abt. 60% in oil suspension), and themixture was refluxed for 2 hours. After cooling, to the reaction mixturewas added isopropyl ether (100 ml) and water (100 ml), and neutralizedby 1N-hydrochloric acid. The organic layer was separated, washed withwater and brine, dried over magnesium sulfate. Magnesium sulfate wasfiltered off, and the filtrate was evaporated under reduced pressure togive a crude red oil. The crude red oil was purified by silica gelchromatography (10:1 hexane-ethyl acetate) to give1-ethynyl-4-(6-methoxyhexyloxy)benzene (2.39 g) as an orange powder.

IR (KBr): 3263.0, 2929.3, 2861.8, 2100.1, 1604.5, 1510.0, 1249.6,1116.6, 840.8 cm⁻¹.

NMR (DMSO-d₆, δ): 1.2-1.6 (6H, m), 1.6-1.8 (2H, m), 3.21 (3H, s), 3.30(2H, t, J=6.4 Hz), 3.97 (2H, t, J=6.4 Hz), 4.00 (1H, s), 6.91 (2H, d,J=8.7 Hz), 7.39 (2H, d, J=8.7 Hz).

MASS (m/z): 233.3 (M⁺+1).

PREPARATION 70

To a solution of 4-methoxycarbonylphenylhydroxyiminomethyl chloride (975mg) and 1-ethynyl-4-(6-methoxyhexyloxy)benzene (1.06 g) intetrahydrofuran (10 ml) was added triethylamine (0.83 ml) intetrahydrofuran (10 ml) over a period of 30 minutes at 40° C., and themixture was stirred at 40° C. for 3 hours and 30 minutes. The mixturewas diluted with dichloromethane and washed with water and brine. Theseparated organic layer was dried over magnesium sulfate and evaporatedunder reduced pressure. The residue was triturated with acetonitrile.The precipitate was collected by filtration and dried to give4-[5-[4-(6-methoxyhexyloxy)phenyl]isoxazol-3-yl]benzoic acid methylester (1.37 g).

IR (KBr): 2937.1, 2859.9, 1716.3, 1278.6, 1116.6 cm⁻¹.

NMR (CDCl₃, δ): 1.3-1.7 (6H, m), 1.7-2.0 (2H, m), 3.34 (3H, s), 3.39(2H, t, J=6.3 Hz), 3.95 (3H, s), 4.02 (2H, t, J=6.4 Hz), 4.00 (1H, s),6.74 (1H, s), 6.98 (2H, d, J=8.8 Hz), 7.77 (2H, d, J=8.8 Hz), 7.94 (2H,d, J=8.4 Hz), 8.14 (2H, d, J=8.4 Hz).

MASS (m/z): 410 (M⁺+1).

PREPARATION 71

To a solution of 4-[5-[4-(6-methoxyhexyloxy)phenyl]isoxazol-3-yl]benzoicacid methyl ester (1.0 g) in a mixture of ethanol (10 ml) andtetrahydrofuran (20 ml) was added 10% sodium hydroxide aqueous solution(4.4 ml) and refluxed for 1 hour. The reaction mixture was adjusted topH 1-2 with 1N-hydrochloric acid, and the resulting precipitate wascollected by filtration to give4-[5-[4-(6-methoxyhexyloxy)phenyl]isoxazol-3-yl]benzoic acid (964.2 mg).

IR (KBr): 2939.0, 2863.8, 2669.0, 2545.6, 1685.5, 1616.1, 1284.4, 1253.5cm⁻¹.

NMR (DMSO-d₆, δ): 1.2-1.6 (6H, m), 1.6-1.9 (2H, m), 3.21 (3H, s), 3.31(2H, t, J=6.2 Hz), 4.04 (2H, t, J=6.4 Hz), 6.11 (2H, d, J=8.8 Hz), 7.54(1H, s), 7.85 (2H, d, J=8.7 Hz), 8.07 (2H, d, J=8.4 Hz), 8.15 (2H, d,J=8.4 Hz).

MASS (m/z): 396 (M⁺+1).

PREPARATION 72

A mixture of 1-bromo-4-fluorobenzene (10 g), cis-2,6-dimethylmorpholine(7.74 ml) and potassium carbonate (15.8 g) in dimethylsulfoxide (50 ml)was stirred for 25 hours at 150° C. The reaction mixture was cooled andpoured into water (500 ml), and stirred for 10 minutes. The reactionmixture was extracted with ethyl acetate (100 ml×2), washed with brine,dried over magnesium sulfate and evaporated under reduced pressure togive a crude yellow oil (680 mg). The crude oil was purified by silicagel chromatography (1:0-10:1 hexane-ethyl acetate) to give4-(4-bromophenyl)-cis-2,6-dimethylmorpholine (360 mg).

IR (KBr): 2971.8, 2871.5, 1821.3, 1494.6, 1452.1, 1241.9, 1176.4,1145.5, 1085.7 cm⁻¹.

NMR (CDCl₃, δ): 1.25 (6H, d, J=6.3 Hz), 2.39 (2H, t, J=11.2 Hz), 3.39(2H, d, J=10.4 Hz), 3.7-3.9 (2H, m), 6.77 (2H, d, J=9.0 Hz), 7.34 (2H,d, J=9.0 Hz).

MASS (m/z): 270 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 68.

PREPARATION 734-[4-(cis-2,6-Dimethylmorpholin-4-yl)phenyl]-2-methyl-3-butyn-2-ol

IR (KBr): 3326.6, 2979.5, 2931.3, 2873.4, 2832.9, 2223.5, 1606.4,1511.9, 1454.1, 1376.9, 1334.5, 1238.1, 1174.4, 1151.3, 1081.9 cm⁻¹.

NMR (DMSO-d₆, δ): 1.14 (6H, d, J=6.1 Hz), 1.44 (6H, s), 2.25 (2H, dd,J=11.0 and 12.3 Hz), 3.5-3.8 (4H, m), 5.34 (1H, s), 6.90 (2H, d, J=8.9Hz), 7.21 (2H, d, J=8.8 Hz).

MASS (m/z): 274 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 69.

PREPARATION 74 4-(4-Ethynylphenyl)-cis-2,6-dimethylmorpholine

IR (KBr): 3313.1, 2933.2, 2869.6, 2852.2, 2102.0, 1602.6, 1243.9,1145.5, 1078.0 cm⁻¹.

NMR (DMSO-d₆, δ): 1.15 (6H, d, J=6.1 Hz), 2.27 (2H, t, J=11.7 Hz),3.6-3.8 (4H, m), 3.93 (1H, s), 6.91 (2H, d, J=8.9 Hz), 7.30 (2H, d,J=8.8 Hz).

MASS (m/z): 344 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 70.

PREPARATION 754-[5-[4-(cis-2,6-Dimethylmorpholin-4-yl)phenyl]isoxazol-3-yl]benzoicacid methylester

IR (KBr): 2973.7, 2873.4, 1718.3, 1614.1, 1510.0, 1450.2, 1278.6,1241.9, 1178.3, 1106.9, 1089.6 cm⁻¹.

NMR (CDCl₃, δ): 1.18 (6H, d, J=6.1 Hz), 2.36 (2H, t, J=11.0 Hz), 3.6-3.9(4H, m), 3.90 (3H, s), 7.11 (2H, d, J=8.9 Hz), 7.48 (1H, s), 7.76 (2H,d, J=8.8 Hz), 8.06 (2H, d, J=8.3 Hz), 8.11 (2H, d, J=8.6 Hz).

MASS (m/z): 393 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 71.

PREPARATION 764-[5-[4-(cis-2,6-Dimethylmorpholin-4-yl)phenyl]isoxazol-3-yl]benzoicacid

IR (KBr): 3430, 2975, 2857, 2652, 2530, 1689, 1614, 1508, 1450, 1240,1176 cm⁻¹.

NMR (DMSO-d₆, δ): 1.18 (6H, d, J=6.0 Hz), 2.36 (2H, t, J=11.1 Hz),3.4-4.0 (5H, m), 7.11 (2H, d, J=8.9 Hz), 7.46 (1H, s), 7.76 (2H, d,J=8.7 Hz), 8.03 (2H, d, J=8.4 Hz), 8.09 (2H, d, J=8.4 Hz).

MASS (m/z): 379 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 66.

PREPARATION 77 1-Bromo-4-(8-bromooctyloxy)benzene

IR (KBr): 1937.1, 2856.1, 1490.7, 1471.4, 1290.1, 1247.7, 1014.4 cm⁻¹.

NMR (DMSO-d₆, δ): 1.2-1.6 (8H, m), 1.6-2.0 (4H, m), 3.52 (2H, t, J=6.7Hz), 3.94 (2H, t, J=6.4 Hz), 6.89 (2H, d, J=8.9 Hz), 7.42 (2H, d, J=8.9Hz).

The following compound was obtained according to a similar manner tothat of Preparation 67.

PREPARATION 78 4-[8-(4-Bromophenoxy)octyl]-cis-2,6-dimethylmorpholine

IR (KBr): 2933.2, 2867.6, 2850.3, 1490.7, 1471.4, 1238.1, 1145.5, 1076.1cm⁻¹.

NMR (DMSO-d₆, δ): 1.02 (6H, d, J=6.3 Hz), 1.2-1.8 (14H, m), 2.1-2.3 (2H,m), 2.69 (2H, d, J=10.4 Hz), 3.4-3.6 (2H, m), 3.93 (2H, t, J=6.4 Hz),6.89 (2H, d, J=8.9 Hz), 7.42 (2H, d, J=8.9 Hz).

MASS (m/z): 398 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 68.

PREPARATION 794-[4-[8-(cis-2,6-Dimethylmorpholin-4-yl)octyloxy]phenyl]-2-methyl-3-butyn-2-ol

IR (KBr): 3187.8, 2973.7, 2933.2, 2858.0, 1602.6, 1506.1, 1469.5,1241.9, 1164.8, 1139.7, 1081.9 cm⁻¹.

NMR (DMSO-d₆, δ): 1.02 (6H, d, J=6.3 Hz), 1.2-1.8 (20H, m), 2.1-2.3 (2H,m), 2.69 (2H, d, J=10.4 Hz), 3.4-3.7 (2H, m), 3.95 (2H, t, J=6.4 Hz),5.38 (1H, s), 6.89 (2H, d, J=8.8 Hz), 7.29 (2H, d, J=8.7 Hz).

MASS (m/z): 402 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 69.

PREPARATION 80 4-[8-(4-Ethynylphenoxy)octyl]-cis-2,6-dimethylmorpholine

IR (KBr): 3313.1, 2933.2, 2869.6, 2852.2, 2102.0, 1602.6, 1243.9,1145.5, 1078.0 cm⁻¹.

NMR (DMSO-d₆, δ): 1.02 (6H, d, J=6.3 Hz), 1.2-1.8 (14H, m), 2.1-2.3 (2H,m), 2.69 (2H, d, J=10.4 Hz), 3.4-3.7 (2H, m), 3.97 (2H, t, J=6.5 Hz),4.00 (1H, s), 6.91 (2H, d, J=8.7 Hz), 7.38 (2H, d, J=8.7 Hz).

MASS (m/z): 344 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 70.

PREPARATION 814-[5-[4-[8-(cis-2,6-Dimethylmorpholin-4-yl)octyloxy]phenyl]isoxazol-3-yl]benzoicacid methyl ester

IR (KBr): 2931.3, 2871.5, 2850.3, 1714.4, 1618.0, 1508.1, 1272.8 cm⁻¹.

NMR (CDCl₃, δ): 1.16 (6H, d, J=6.3 Hz), 1.2-2.0 (14H, m), 2.2-2.4 (2H,m), 2.75 (2H, d, J=10.5 Hz), 3.6-3.8 (2H, m), 3.96 (3H, s), 4.02 (2H, t,J=6.5 Hz), 6.74 (1H, s), 6.99 (2H, d, J=8.8 Hz), 7.77 (2H, d, J=8.8 Hz),7.94 (2H, d, J=8.3 Hz), 8.15 (2H, d, J=8.3 Hz).

MASS (m/z): 521 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 71.

PREPARATION 824-[5-[4-[8-(cis-2,6-Dimethylmorpholin-4-yl)octyloxy]phenyl]isoxazol-3-yl]benzoicacid

IR (KBr): 3444.2, 2942.8, 2634.3, 2520.5, 1697.1, 1618.0 1452.1, 1278.6,1259.3, 1180.2 cm⁻¹.

NMR (CDCl₃, δ): 1.12 (6H, d, J=6.3 Hz), 1.2-1.9 (14H, m), 2.3-2.7 (2H,m), 2.8-3.2 (2H, m), 3.7-4.0 (2H, m), 4.0-4.2 (2H, m), 7.12 (2H, d,J=8.8 Hz), 7.56 (1H, s), 7.86 (2H, d, J=8.7 Hz), 8.04 (2H, d, J=8.5 Hz),8.10 (2H, d, J=8.5 Hz).

MASS (m/z): 493 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 67.

PREPARATION 83 1-Bromo-4-(7-methoxyheptyloxy)benzene

NMR (DMSO-d₆, δ): 1.2-1.6 (8H, m), 1.6-1.8 (2H, m), 3.20 (3H, s), 3.29(2H, t, J=6.4 Hz), 3.96 (2H, t, J=6.4 Hz), 5.39 (1H, s), 6.89 (2H, d,J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz).

MASS (m/z): 301 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 68.

PREPARATION 84 4-[4-(7-Methoxyheptyloxy)phenyl]-2-methyl-3-butyn-2-ol

IR (KBr): 3394.1, 3309.2, 2979.5, 2939.0, 2871.5, 2852.2, 1606.4,1510.0, 1469.5, 1247.7, 1160.9 cm⁻¹.

NMR (DMSO-d₆, δ): 1.2-1.6 (14H, m), 1.6-1.8 (2H, m), 3.20 (3H, s), 3.29(2H, t, J=6.4 Hz), 3.93 (2H, t, J=6.5 Hz), 6.89 (2H, d, J=9.0 Hz), 7.42(2H, d, J=9.0 Hz).

MASS (m/z): 305.2 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 69.

PREPARATION 85 1-Ethynyl-4-(7-methoxyheptyloxy)benzene

IR (KBr): 3313.1, 3290.0, 2935.1, 2859.9, 2105.9, 1606.4, 1506.1,1247.7, 1114.7 cm⁻¹.

NMR (DMSO-d₆, δ): 1.2-1.6 (8H, m), 1.6-1.8 (2H, m), 3.20 (3H, s), 3.29(2H, t, J=6.4 Hz), 3.97 (2H, t, J=6.5 Hz), 6.92 (2H, d, J=8.9 Hz), 7.39(2H, d, J=8.8 Hz).

MASS (m/z): 247.2 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 70.

PREPARATION 86 4-[5-[4-(7-Methoxyheptyloxy)phenyl]isoxazol-3-yl]benzoicacid methyl ester

IR (KBr): 2935.1, 2861.8, 1720.2, 1618.0, 1436.7, 1276.6, 1112.7 cm⁻¹.

NMR (CDCl₆, δ): 1.2-1.7 (8H, m), 1.7-2.0 (2H, m), 3.34 (3H, s), 3.38(2H, t, J=6.5 Hz), 3.96 (3H, s), 4.02 (2H, t, J=6.4 Hz), 6.75 (1H, s),6.99 (2H, d, J=8.9 Hz), 7.77 (2H, d, J=8.8 Hz), 7.94 (2H, d, J=8.5 Hz),8.15 (2H, d, J=8.4 Hz).

MASS (m/z): 424 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 71.

PREPARATION 87 4-[5-[4-(7-Methoxyheptyloxy)phenyl]isoxazol-3-yl]benzoicacid

IR (KBr): 2933.2, 2856.1, 2669.0, 2549.1, 1683.6, 1614.1, 1506.1,1454.1, 1427.1, 1284.4, 1257.4, 1120.4 cm⁻¹.

NMR (DMSO-d₆, δ): 1.2-1.6 (5H, m), 1.7-1.9 (2H, m), 3.21 (3H, s),3.2-3.5 (2H, m), 4.0-4.2 (2H, m), 7.0-7.2 (2H, m), 7.5 (1H, s), 7.8-8.0(2H, m), 8.0-8.2 (4H, m).

MASS (m/z): 410 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 66.

PREPARATION 88 1-Bromo-4-(7-bromoheptyloxy)benzene

IR (KBr): 2939.0, 2910.1, 2856.1, 1591.0, 1488.8, 1467.6, 1288.2, 1245.8cm⁻¹.

NMR (DMSO-d₆, δ): 1.2-1.5 (6H, m), 1.6-1.9 (4H, m), 3.53 (2H, t, J=6.7Hz), 3.94 (2H, t, J=6.5 Hz), 6.90 (2H, d, J=9.0 Hz), 7.42 (2H, d, J=9.0Hz).

MASS (m/z): 350 (M⁺).

PREPARATION 89

A mixture of 1-bromo-4-(7-bromoheptyloxy)benzene (4.405 g),cis-2,6-dimethylmorpholine (1.55 ml) and potassium carbonate (2.09 g) inN,N-dimethylformamide (22 ml) was stirred for 1 hour at 70° C. To thereaction mixture was added cis-2,6-dimethylmorpholine (7.75 ml) andstirred for 1 hour at 70° C. Ethyl acetate (100 ml) was added, and themixture washed with water (50 ml×2) and brine. The separated organiclayer was dried over magnesium sulfate and evaporated under reducedpressure to give a crude pale yellow oil (5.30 g). The crude oil waspurified by silica gel chromatography (20:1-1:2 hexane-ethyl acetate) togive 4-[7-(4-bromophenoxy)heptyl]-cis-2,6-dimethylmorpholine (4.43 g) asa pale yellow oil.

IR (KBr): 2971.8, 2935.1, 2859.9, 2811.7, 2773.1, 1488.8, 1469.5,1243.9, 1145.5, 1078 cm⁻¹.

NMR (DMSO-d₆, δ): 1.02 (6H, d, J=6.3 Hz), 1.2-1.8 (12H, m), 2.1-2.3 (2H,m), 2.69 (2H, d, J=10.5 Hz), 3.4-3.6 (2H, m), 3.94 (2H, t, J=6.4 Hz),6.89 (2H, d, J=8.9 Hz), 7.42 (2H, d, J=8.9 Hz).

MASS (m/z): 386 (M⁺+2).

The following compound was obtained according to a similar manner tothat of Preparation 68.

PREPARATION 904-[4-[7-(cis-2,6-Dimethylmorpholin-4-yl)heptyloxy]phenyl]-2-methyl-3-butyn-2-ol

IR (KBr): 3151.1, 2973.7, 2935.1, 2859.9, 2825.2, 1604.5, 1506.1,1243.9, 1160.9, 1139.7 cm⁻¹.

NMR (DMSO-d₆, δ): 1.02 (6H, d, J=6.3 Hz), 1.2-1.8 (18H, m), 2.1-2.3 (2H,m), 2.69 (2H, d, J=10.2 Hz), 3.4-3.7 (2H, m), 3.95 (2H, t, J=6.4 Hz),5.39 (1H, s), 6.89 (2H, d, J=8.7 Hz), 7.28 (2H, d, J=8.6 Hz).

MASS (m/z): 388 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 69.

PREPARATION 91 4-[7-(4-Ethynylphenoxy)heptyl]-cis-2,6-dimethylmorpholine

IR (KBr): 3290.0, 2971.8, 2935.1 2859.9, 2811.7, 2775.1, 2105.9, 1606.4,1506.1, 1469.5, 1288.2, 1247.7, 1170.6, 1145.5, 1079.9, 833.1 cm⁻¹.

NMR (DMSO-d₆, δ): 1.02 (6H, d, J=6.3 Hz), 1.2-1.8 (12H, m), 2.1-2.3 (2H,m), 2.69 (2H, d, J=10.3 Hz), 3.4-3.6 (2H, m), 3.95 (2H, t, J=6.5 Hz),4.00 (1H, s), 6.92 (2H, d, J=8.8 Hz), 7.39 (2H, d, J=8.7 Hz).

MASS (m/z): 330 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 70.

PREPARATION 924-[5-[4-[7-(cis-2,6-Dimethylmorpholin-4-yl)heptyloxy]phenyl]isoxazol-3-yl]benzoicacid methyl ester

IR (KBr): 2946.7, 2931.3, 2869.6, 2815.6, 2767.3, 1720.2, 1616.1,1506.1, 1450.2, 1434.8, 1307.5, 1270.9, 1178.3, 1143.6, 1105.0 1078.0cm⁻¹.

NMR (CDCl₃, δ): 1.16 (6H, d, J=6.3 Hz), 1.2-2.0 (12H, m), 2.2-2.4 (2H,m), 2.75 (2H, d, J=10.4 Hz), 3.5-3.9 (2H, m), 3.96 (3H, s), 4.02 (2H, t,J=6.5 Hz), 6.75 (1H, s), 6.99 (2H, d, J=8.8 Hz), 7.77 (2H, d, J=8.8 Hz),7.94 (2H, d, J=8.5 Hz), 8.15 (2H, d, J=8.4 Hz).

MASS (m/z): 507 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 71.

PREPARATION 934-[5-[4-[7-(cis-2,6-Dimethylmorpholin-4-yl)heptyloxy]phenyl]isoxazol-3-yl]benzoicacid

IR (KBr): 3446.2, 2939.0, 2636.2, 2520.5, 1693.2, 1618.0, 1508.1,1452.1, 1265.1 cm⁻¹.

NMR (DMSO-d₆, δ): 1.12 (6H, d, J=6.2 Hz), 1.2-1.9 (12H, m), 2.3-2.7 (2H,m), 2.8-3.2 (2H, m), 3.7-4.0 (2H, m), 4.07 (2H, t, J=6.3 Hz), 7.13 (2H,d, J=8.8 Hz), 7.55 (1H, s), 7.86 (2H, d, J=8.5 Hz), 8.04 (2H, d, J=8.5Hz), 8.10 (2H, d, J=8.4 Hz).

MASS (m/z): 507 (M⁺+1).

PREPARATION 94

To a solution of 4-hydroxypiperidine (15 g) in a mixture oftetrahydrofuran (THF) (150 ml) and water (100 ml) was added dropwise asolution of di-tert-butyl dicarbonate (48.5 g) in THF (100 ml) keepingpH 9 with 1N-sodium hydroxide under ice-cooling. The mixture was stirredat ambient temperature for 1 hour. The reaction mixture was successivelywashed with water and saturated sodium chloride, dried over anhydrousmagnesium sulfate. Magnesium sulfate was filtered off, and the filtratewas evaporated under reduced pressure to give crystals. The crystalswere washed with n-hexane (300 ml), collected by filtration and dried invacuo to give 1-N-t-butyloxycarbonyl-4-hydroxypiperidine (24.66 g).

PREPARATION 95

To a solution of 1-N-t-butyloxycarbonyl-4-hydroxypiperidine (5.0 g) indimethylformamide (DMF) (25 ml) was portionwise added sodium hydride(60% in oil) (1.29 g) with stirring under ice-cooling. The mixture wassuccessively stirred at ambient temperature for 30 minutes, stirred at60° C. for 1 hour and cooled with an ice bath. To the reaction mixturewas added 1,5-dibromopentane (6.72 ml), and the mixture was stirred atambient temperature for 3 hours. The reaction solution was poured intowater (100 ml) and extracted twice with a mixture of ethyl acetate (80ml) and n-hexane (30 ml). The extract was washed with saturated aqueoussodium chloride, dried over magnesium sulfate and evaporated in vacuo.The resulting residue was chromatographed on silica gel (200 ml) elutingwith a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractionscontaining the desired compound were collected and evaporated underreduced pressure to give4-(5-bromopentyloxy)-1-N-t-butyloxycarbonylpiperidine (2.44 g).

NMR (CDCl₃, δ): 1.46 (9H, s), 1.50-1.70 (6H, m), 1.70-1.96 (4H, m),3.00-3.15 (2H, m), 3.35-3.50 (5H, m), 3.70-3.90 (2H, m).

APCI MASS (m/z): 250 (M⁺−101).

PREPARATION 96

To a solution of 4-(5-bromopentyloxy)-1-N-t-butyloxycarbonylpiperidine(2.44 g) in methanol (13 ml) was added 28% sodium methoxide methanolsolution (14.2 ml), and the mixture was stirred under reflux for 4hours. The reaction mixture was evaporated in vacuo. The resultingresidue was chromatographed on silica gel (250 ml) eluting with amixture of n-hexane and ethyl acetate (5:1 v/v). The fractionscontaining the object compound were collected and evaporated underreduced pressure to give4-(5-methoxypentyloxy)-1-N-t-butyloxycarbonylpiperidine (1.97 g).

NMR (CDCl₃, δ): 1.45 (9H, s), 1.45-1.95 (10H, m), 3.03 (1H, dd, J=3.47and 9.20 Hz), 3.10 (1H, dd, J=3.47 and 9.20 Hz), 3.44 (3H, s), 3.34-3.50(5H, m), 3.70-3.85 (2H, m).

APCI MASS (m/z): 202 (M⁺−101).

PREPARATION 97

To a solution of 4-(5-methoxypentyloxy)-1-N-t-butyloxycarbonylpiperidine(1.97 g) in ethyl acetate (20 ml) was added 4N-hydrogen chloride ethylacetate solution (16.3 ml), and the mixture was stirred at ambienttemperature for 2 hours. The reaction mixture was evaporated in vacuo.The resulting residue was dissolved in a mixture of dichloromethane andmethanol (10:1; 50 ml:5 ml). To this solution was added 1N-sodiumhydroxide (5 ml) with stirring. The organic layer was separated andevaporated under reduced pressure to give4-(5-methoxypentyloxy)piperidine (0.62 g).

NMR (CDCl₃, δ): 1.25-1.50 (2H, s), 1.50-1.75 (6H, m), 1.90-2.10 (2H, m),2.70-2.90 (2H, m), 2.95-3.20 (2H, m), 3.33 (3H, s), 3.35-3.50 (5H, m).

APCI MASS (m/z): 202 (M⁺).

PREPARATION 98

A solution of 4-fluorobenzonitrile (0.38 g),4-(5-methoxypentyloxy)piperidine (0.62 g) and potassium carbonate (0.87g) in DMF (8 ml) was stirred at 90-95° C. for 6 hours. The reactionmixture was poured into water (50 ml) and extracted twice with a mixtureof ethyl acetate and n-hexane (50 ml:20 ml). The extracts were combined,washed with saturated aqueous sodium chloride, dried over magnesiumsulfate and evaporated in vacuo. The resulting residue waschromatographed on silica gel (100 ml) eluting with a mixture ofn-hexane and ethyl acetate (5:1 v/v-2:1 v/v). The fractions containingthe desired compound were collected and evaporated under reducedpressure to give 4-(5-methoxypentyloxy)-N-(4-cyanophenyl)piperidine (294mg).

NMR (CDCl₃, δ): 1.35-1.55 (2H, s), 1.55-1.75 (5H, m), 1.85-2.05 (2H, m),3.13 (1H, dd, J=3.47 and 9.20 Hz), 3.17 (1H, dd, J=3.47 and 9.20 Hz),3.33 (3H, s), 3.35-3.75 (8H, m), 6.85 (2H, d, J=9.0 Hz), 7.47 (2H, d,J=8.96 Hz).

APCI MASS (m/z): 303 (M⁺).

PREPARATION 99

A solution of 4-(5-methoxypentyloxy)-N-(4-cyanophenyl)piperidine (294mg) and thiosemicarbazide (0.68 g) in toluene (20 ml) andtrifluoroacetic acid (10 ml) was stirred at 60-65° C. for 7 hours. Aftercooling, the reaction mixture was poured into a mixture of water (100ml) and ethyl acetate (200 ml) and adjusted to pH 10 with 1N-sodiumhydroxide. The mixture was dissolved in a mixture of THF (50 ml) andmethanol (10 ml). The organic layer was separated, washed with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate andevaporated in vacuo. The resulting precipitate was washed with isopropylether and dried in vacuo to give2-amino-5-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]-1,3,4-thiadiazole(1.29 g).

NMR (CDCl₃+CD₃OD, δ): 1.30-1.50 (2H, m), 1.50-1.80 (6H, m), 1.90-2.10(2H, m), 2.90-3.10 (2H, m), 3.34 (3H, s), 3.35-3.70 (7H, m), 6.93 (2H,d, J=8.91 Hz), 7.63 (2H, d, J=8.83 Hz).

APCI MASS (m/z): 377 (M⁺).

PREPARATION 100

To a suspension of2-amino-5-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]-1,3,4-thiadiazole(1.29 g) in ethanol (20 ml) was added ethyl 4-bromoacetylbenzoate (1.39g) and stirred at reflux for 5 hours. The reaction mixture was cooledand poured into diisopropyl ether (IPE) (60 ml). The resultingprecipitate was collected by filtration and dried. To a suspension ofthe precipitate in xylene (40 ml) was added trifluoroacetic acid (4 ml),and the mixture was stirred at reflux (130° C.) for 5 hours. Thereaction mixture was cooled and poured into IPE (300 ml). The resultingprecipitate was filtered and dried to give4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid ethyl ester trifluroacetic acid salt (2.01 g).

NMR (CDCl₃, δ): 1.42 (3H, t, J=7.12 Hz), 1.45-1.75 (6H, m), 1.85-2.10(2H, m), 2.30-2.50 (2H, m), 3.36 (3H, s), 3.35-3.55 (5H, m), 3.60-3.80(2H, m), 4.40 (2H, q, J=7.14 Hz), 7.57 (2H, d, J=8.78 Hz), 7.84 (2H, d,J=8.40 Hz), 7.91 (2H, d, J=8.79 Hz), 8.13 (1H, s).

ESI MASS (m/z): 549 (M⁺+1).

PREPARATION 101

To a solution of4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid ethyl ester trifluroacetic acid salt (2.01 g) in a mixture ofmethanol (40 ml) and tetrahydrofuran (20 ml) was added 4N-NaOR (20 ml),and the mixture was refluxed for 6 hours. The reaction mixture wascooled, poured into water (200 ml) and adjusted to pH 2 with conc. HCl.The resulting precipitate was collected by filtration, washed in turnwith water, isopropyl alcohol (30 ml) and IPE (50 ml) to give4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid (1.28 g).

ESI MASS (m/z) (Negative): 519.2 (M⁺+1).

PREPARATION 102

To a solution of4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid (1.28 g) and 1-hydroxybenzotriazole (465 mg) in dichloromethane (50ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimidehydrochloride (WSCD.HCl) (943 mg), and the mixture was stirred overnightat ambient temperature. The reaction mixture was evaporated in vacuo. Tothe resulting precipitate was added water (50 ml), and the solid waswashed with water and IPE (50 ml) and dried under reduced pressure for 3hours to give4-[2-[4-[4-(5-methoxypentyloxy)piperidin-1-yl]phenyl]imdazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid benzotriazol-1-yl ester (1.26 g).

IR (KBr): 1774.2, 1708.6, 1604.5, 1471.4 1365.4, 1230.4 cm⁻¹.

NMR (CDCl₃, δ): 1.30-1.80 (8H, m), 1.85-2.10 (2H, m), 3.05-3.30 (2H, m),3.33 (3H, s), 3.35-3.55 (4H, m), 3.55-3.75 (2H, m), 6.94 (2H, d, J=8.94Hz), 7.30-7.60 (3H, m), 7.73 (2H, d, J=8.79 Hz), 8.00-8.20 (4H, m), 8.30(2H, d, J=8.46 Hz).

ESI MASS (m/z) (Positive): 660.1 (M⁺+Na).

PREPARATION 103

To a solution of 4-hydroxy-N-(benzyloxycarbonyl)piperidine (5.0 g) inTHF (50 ml) were added 3-bromocyclohexene (3.67 ml) and silver oxide(7.4 g). The mixture was stirred at ambient temperature overnight. Tothe solution were added 3-bromocyclohexene (4.0 ml) and silver oxide(5.0 g), and the mixture was stirred at 40° C. for 6 hours. The reactionmixture was filtered, and the filtrate was evaporated in vacuo. Theresulting residue was chromatographed on silica gel (300 ml) elutingwith a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractionscontaining the desired compound were collected and evaporated underreduced pressure to give4-(2-cyclohexenyloxy)-N-(benzyloxycarbonyl)piperidine (3.83 g).

NMR (CDCl₃, δ): 1.40-2.20 (12H, m), 3.10-3.30 (2H, m), 3.50-3.70 (1H,m), 3.80-4.10 (3H, m), 5.12 (2H, s), 5.40-5.90 (2H, m), 7.35 (5H, m).

ESI MASS (m/z) (Positive): 338.3 (M⁺+Na).

PREPARATION 104

A solution of 4-(2-cyclohexenyloxy)-N-(benzyloxycarbonyl)piperidine(3.80 g), and 10% palladium on carbon (50% wet) (1.0 g) in methanol (40ml) was hydrogenated under an atmospheric pressure of hydrogen atambient temperature for 6 hours. The catalyst was filtered off, and thefiltrate was evaporated in vacua and dried in vacuo to give4-(cyclohexyloxy)piperidine (2.42 g).

NMR (CDCl₃, δ): 1.10-1.40 (4H, m), 1.40-2.00 (10H, m), 2.60-2.90 (2H,m), 3.05-3.20 (2H, m), 3.30-3.50 (1H, m), 3.50-3.75 (1H, m).

APCI MASS (m/z): 184.4 (M⁺+1).

PREPARATION 105

A solution of 4-fluorobenzonitrile (1.50 g), 4-(cyclohexyloxy)piperidine(2.40 g) and potassium carbonate (3.3 g) in DMF (30 ml) was stirred at90-95° C. for 6 hours. The reaction mixture was poured into water (100ml) and extracted twice with a mixture of ethyl acetate and n-hexane (80ml:30 ml). The extracts were combined, washed with saturated aqueoussodium chloride, dried over magnesium sulfate and evaporated in vacuo.The resulting residue was chromatographed on silica gel (200 ml) elutingwith a mixture of n-hexane and ethyl acetate (6:1 v/v-5:1 v/v). Thefractions containing the desired compound were collected and evaporatedunder reduced pressure to give4-[4-cyclohexyloxypiperidin-1-yl)benzonitrile (1.90 g).

NMR (CDCl₃, δ): 1.10-1.40 (5H, m), 1.40-2.00 (9H, m), 3.00-3.20 (2H, m),3.20-3.45 (1H, m), 3.55-3.80 (3H, m), 6.85 (2H, d, J=8.99 Hz), 7.46 (2H,d, J=8.95 Hz).

APCI MASS (m/z): 285 (M⁺).

PREPARATION 106

A solution of 4-(4-cyclohexyloxypiperidin-1-yl)benzonitrile (1.90 g),thiosemicarbazide (0.91 g) in toluene (20 ml) and trifluroacetic acid(10 ml) was stirred at 60-65° C. with stirring for 7 hours. Aftercooling, the reaction mixture was poured into a mixture of water (100ml) and ethyl acetate (100 ml) and adjusted to pH 10 with 1N-sodiumhydroxide. The mixture was dissolved in a mixture of THF (50 ml) andethyl acetate (100 ml). The organic layer was separated, washed withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and evaporated in vacuo. The resulting precipitate was washeddiisopropyl ether and dried in vacuo to give2-amino-5-[4-[4-(cyclohexyloxy)piperidin-1-yl]phenyl]-1,3,4-thiadiazole(1.72 g).

NMR (DMSO-d₆, δ): 1.10-1.45 (4H, m), 1.45-1.95 (10H, m), 2.85-3.10 (2H,m), 3.25-3.45 (1H, m), 3.50-3.80 (3H, m), 6.97 (2H, d, J=8.92 Hz), 7.54(2H, d, J=8.80 Hz).

APCI MASS (m/z): 360 (M⁺+1).

PREPARATION 107

To a suspension of2-amino-5-[4-[4-(cyclohexyloxy)piperidin-1-yl]phenyl]-1,3,4-thiadiazole(1.72 g) in ethanol (30 ml) was added ethyl 4-bromoacetylbenzoate (1.95g) and the mixture was stirred at reflux for 5 hours. The reactionmixture was cooled and poured into IPE (60 ml). The resultingprecipitate was collected by filtration and dried. To a suspension ofthe precipitate in xylene (40 ml) was added trifluoroacetic acid (4 ml),and the mixture was stirred at reflux (130° C.) for 5 hours. Thereaction mixture was cooled and poured into IPE (300 ml). The resultingprecipitate was filtered and dried to give4-[2-[4-[4-(cyclohexyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]-thiadiazol-6-yl]benzoicacid ethyl ester trifluoroacetic acid salt (2.01 g). This compound wasimmediately used as the starting compound for the next step.

The following compound was obtained according to a similar manner tothat of Preparation 101.

PREPARATION 1084-[2-[4-[4-(Cyclohexyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid

NMR (CDCl₃+CD₃OD, δ): 1.10-2.10 (14H, m), 2.90-3.20 (2H, m), 4.20-4.60(1H, m), 6.96 (2H, d, J=8.24 Hz), 7.50-8.20 (7H, m).

ESI MASS (m/z): 525.3 (M⁺+Na).

The following compound was obtained according to a similar manner tothat of Preparation 102.

PREPARATION 1094-[2-[4-[4-(Cyclohexyloxy)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1772, 1703, 1606, 1470, 1369 cm⁻¹.

PREPARATION 110

To a solution of 4-(4-methanesulfonyloxypiperidin-1-yl)benzonitrile(4.90 g) in N,N-dimethylformamide (DMF) (50 ml) were added potassiumcarbonate (4.83 g) and 2,6-dimethylmorpholine (3.02 g), and the mixturewas stirred at 90-95° C. for 6 hours. After cooling, the reactionmixture was poured into water (300 ml) and extracted twice with amixture of ethyl acetate and n-hexane (100 ml:30 ml). The extracts werecombined and washed in turn with water and saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and evaporated invacuo. The resulting precipitates were washed with IPE (100 ml),collected by filtration and dried in vacuo to give4-[4-(2,6-dimethylmorpholin-4-yl)piperidin-1-yl]benzonitrile (2.29 g).

NMR (CDCl₃, δ): 1.18 (6H, d, J=6.03 Hz), 1.60-1.90 (2H, m), 1.90-2.15(2H, m), 2.35-2.60 (2H, m), 3.10-3.30 (2H, m), 3.40-4.10 (6H, m),4.80-5.05 (1H, m), 6.87 (2H, d, J=8.97 Hz), 7.48 (2H, d, J=8.96 Hz).

APCI MASS (m/z): 300 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 99.

PREPARATION 1112-Amino-5-[4-[4-(2,6-dimethylmorpholin-4-yl)piperidin-1-yl]phenyl]-1,3,4-thiadiazole

NMR (CDCl₃, δ): 1.19 (6H, d, J=6.22 Hz), 1.70-2.15 (4H, m), 3.10-3.25(2H, m), 3.40-3.70 (4H, m), 3.70-4.10 (2H, m), 4.80-5.00 (1H, m), 6.94(2H, d, J=8.88 Hz), 7.65 (2H, d, J=8.82 Hz).

APCI MASS (m/z): 374 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 100.

PREPARATION 1124-[2-[4-[4-(2,6-Dimethylmorpholin-4-yl)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid ethyl ester trifluoroacetic acid salt

NMR (CDCl₃, δ): 1.19 (6H, d, J=6.20 Hz), 1.41 (3H, t, J=7.11 Hz),1.70-1.90 (2H, m), 1.90-2.20 (2H, m), 2.40-2.65 (2H, m), 3.20-3.40 (2H,m), 3.40-4.30 (8H, m), 4.39 (2H, q, J=7.07 Hz), 4.85-5.10 (1H, m), 7.02(2H, d, J=8.93 Hz), 7.76 (2H, d, J=8.81 Hz), 7.87 (2H, d, J=8.34 Hz),8.08 (1H, s), 8.11 (2H, d, J=9.71 Hz).

The following compound was obtained according to a similar manner tothat of Preparation 101.

PREPARATION 1134-[2-[4-[4-(2,6-Dimethylmorpholin-4-yl)piperidin-1-yl)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid

APCI MASS (m/z): 519 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 102.

PREPARATION 1144-12-[4-[4-(2,6-Dimethylmorpholin-4-yl)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1774, 1691, 1605, 1466, 1429, 1232 cm⁻¹.

PREPARATION 115

A solution of 4-[4-(methanesulfonyloxy)piperidin-1-yl]nitrobenzene (2.0g), and potassium thioacetate (1.14 g) in dimethylsulfoxide (DMSO) (20ml) was stirred at 100-110° C. for 3 hours. The reaction mixture waspoured into water (100 ml) and extracted twice with ethyl acetate (100ml). The extracts were collected, washed with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and evaporated invacuo. The resulting precipitates were washed with IPE (50 ml),collected by filtration and dried in vacuo to give4-(4-acetylthiopiperidin-1-yl)nitrobenzene (1.15 g).

NMR (CDCl₃, δ): 1.60-1.85 (2H, m), 2.00-2.20 (2H, m), 2.34 (3H, s),3.15-3.35 (2H, m), 3.65-3.90 (3H, m), 6.81 (2H, d, J=9.47 Hz), 8.12 (2H,d, J=9.43 Hz).

APCI MASS (m/z): 281 (M⁺).

PREPARATION 116

To a solution of 4-(4-acetylthiopiperidin-1-yl)nitrobenzene (3.34 g) ina mixture of THF (30 ml) and methanol (30 ml) was added 28% sodiummethoxide methanol solution (2.67 ml) at 0-5° C. and stirred at the sametemperature for 30 minutes. To the mixture was added iodopropane (1.51ml) at the same temperature and stirred at ambient temperature for 2hours. The reaction mixture was evaporated in vacuo and dissolved inethyl acetate (100 ml). The solution was washed three times withsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and evaporated in vacuo. A solution of the resulting residue,ammonium chloride (1.0 g) and iron powder (4.0 g) in a mixture ofethanol (60 ml) and water (30 ml) was refluxed for 2 hours. The reactionmixture was evaporated in vacuo. The resulting residue waschromatographed on silica gel (300 ml) eluting with ethyl acetate. Thefractions containing the desired compound were collected and evaporatedunder reduced pressure to give 4-(4-propylthiopiperidin-1-yl)aniline(2.47 g).

NMR (CDCl₃, δ): 1.00 (3H, t, J=7.16 Hz), 1.50-1.90 (4H, m), 1.95-2.15(2H, m), 2.55 (2H, t, J=7.56 Hz), 2.60-2.80 (3H, m), 3.35-3.55 (4H, m),6.63 (2H, d, J=8.81 Hz), 6.81 (2H, d, J=8.80 Hz).

APCI MASS (m/z): 251 (M⁺).

PREPARATION 117

A solution of 4-(4-propylthiopiperidin-1-yl)aniline (2.44 g),1-[2-(p-toluenesulfonyloxy)ethyl]-2-oxazolidone (3.08 g) and potassiumcarbonate (3.28 g) in a mixture of acetonitrile (25 ml) and DMF (13 ml)was stirred at 120° C. for 5 hours. The reaction mixture was poured intowater (100 ml) and extracted twice with ethyl acetate (60 ml). Theextracts were collected, washed twice with saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and evaporated invacuo. The resulting residue was chromatographed on silica gel (200 ml)eluting with ethyl acetate. The fractions containing the desiredcompound were collected and evaporated under reduced pressure to give1-[(2-oxazolidon-3-yl)ethylaminol-4-[4-(propylthio)piperidin-1-yl]benzene(1.98 g).

NMR (CDCl₃, δ): 1.00 (3H, t, J=7.34 Hz), 1.50-1.90 (5H, m), 2.00-2.20(2H, m), 2.55 (2H, t, J=7.5 Hz), 2.55-2.90 (3H, m), 3.10-3.65 (8H, m),4.29 (2H, dd, J=6.56 and 8.29 Hz), 6.40-6.70 (2H, m), 6.70-6.95 (2H, m).

APCI MASS (m/z): 364 (M⁺).

PREPARATION 118

A solution of1-[(2-oxazolidon-3-yl)ethylamino]-4-(4-propylthiopiperidin-1-yl)benzene(1.96 g) in 30% HBr in acetic acid solution (15 ml) was stirred atambient temperature overnight. IPE (100 ml) was added to the reactionmixture, and the resulting precipitates were collected by filtration,washed with IPE (40 ml) and dried under reduced pressure. Theprecipitates were dissolved in a mixture of ethanol (20 ml) andn-butylalcohol (40 ml), and the solution was refluxed for 6 hours. Aftercooling, to the reaction mixture was added IPE (100 ml), and theresulting precipitates were collected by filtration, washed with IPE (20ml) and dried in vacuo to give1-[4-(4-propylthiopiperidin-1-yl)phenyl-1-yl]piperazine (2.51 g).

NMR (CDCl₃+CD₃OD, δ): 1.03 (3H, t, J=6.98 Hz), 1.50-1.90 (2H, m),2.10-2.40 (3H, m), 2.50-2.90 (5H, m), 6.80-7.00 (2H, m), 7.55-7.70 (2H,m).

APCI MASS (m/z): 320 (M⁺).

PREPARATION 119

A solution of 1-[4-(4-propylthiopiperidin-1-yl)benzen-1-yl]piperazine(2.45 g) and potassium carbonate (2.81 g) in N,N-dimethylsulfoxide (30ml) was stirred at 100° C. for 30 minutes and then at 150° C. for 5hours. The reaction mixture was poured into water (100 ml) and extractedtwice with ethyl acetate (100 ml). The extracts were collected, washedtwice with saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and evaporated in vacuo. The resulting residue waschromatographed on silica gel (200 ml) eluting with a mixture ofdichloromethane and methanol (9:1 v/v). The fractions containing thedesired compound were collected and evaporated under reduced pressureand washed with IPE. The precipitates were collected by filtration anddried in vacuo to give4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acidethyl ester (1.22 g).

NMR (CDCl₃, δ): 1.01 (3H, t, J=7.36 Hz), 1.37 (3H, t, J=7.79 Hz),1.50-1.90 (4H, m), 2.00-2.20 (2H, m), 2.56 (2H, t, J=7.53 Hz), 2.65-2.90(3H, m), 3.15-3.30 (4H, m), 3.40-3.60 (6H, m), 4.33 (2H, q, J=7.11 Hz),6.91 (2H, d, J=9.10 Hz), 6.92 (4H, s), 7.95 (2H, d, J=8.97 Hz).

APCI MASS (m/z): 468 (M⁺).

PREPARATION 120

To a solution of4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acidethyl ester (1.22 g) in a mixture of ethanol (10 ml) and tetrahydrofuran(40 ml) was added 10% aqueous NaOH (2.1 ml) and 1N-NaOR (10 ml), and themixture was refluxed for 6 hours. The reaction mixture was cooled andadjusted to pH 2.5-3.0 with 1N-HCl. The resulting precipitates werecollected by filtration, washed in turn with water (30 ml) and IPE (50ml) and dried in vacuo to give4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acid(0.99 g).

NMR (DMSO-d₆, δ): 0.94 (3H, t, J=7.38 Hz), 1.40-1.70 (5H, m), 1.85-2.15(2H, m), 2.60-2.90 (4H, m), 3.00-3.20 (5H, m), 3.30-3.55 (6H, m), 6.88(4H, s), 7.01 (2H, d, J=9.00 Hz), 7.78 (2H, d, J=8.89 Hz).

APCI MASS (m/z): 440 (M⁺).

PREPARATION 121

To a solution of4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl]piperazin-4-yl]benzoic acid(0.98 g), 1-hydroxybenzotriazole (0.39 g) in dichloromethane (20 ml) wasadded 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride(WSCD.HCl) (0.85 g), and the mixture was stirred for 15 minutes. To thesolution was added triethylamine (0.31 ml), and the mixture was stirredovernight at ambient temperature. The reaction mixture was poured into amixture of 0.1N-hydrochloric acid (25 ml) and dichloromethane (60 ml).The organic layer was washed with water and saturated aqueous sodiumchloride, dried over anhydrous magnesium sulfate and evaporated invacuo. To the resulting precipitates were washed with water and IPE (50ml), collected by filtration and dried under reduced pressure to give4-[1-[4-(4-propylthiopiperidin-1-yl)phenyl)piperazin-4-yl]benzoic acidbenzotriazol-1-yl ester (1.04 g).

NMR (CDCl₃, δ): 1.01 (3H, t, J=7.36 Hz), 1.50-1.90 (5H, m), 2.00-2.20(2H, m), 2.56 (2H, t, J=7.56 Hz), 2.65-2.90 (3H, m), 3.20-3.30 (4H, m),3.45-3.70 (6H, m), 6.94 (4H, s), 7.00 (2H, d, J=9.19 Hz), 7.35-7.60 (3H,m), 8.05-8.20 (3H, m).

APCI MASS (m/z): 557 (M⁺).

PREPARATION 122

To a solution of N-t-butyloxycarbonyl-4-acetylthiopiperidine (5.5 g) ina mixture of THF (50 ml) and methanol (50 ml) was added 28% sodiummethoxide methanol solution (4.76 ml) with stirring under ice-coolingand stirred at the same temperature for 30 minutes. To the solution wasadded 1,6-dibromohexane (17.1 g) under ice-cooling, and the mixture wassuccessively stirred at ambient temperature for 30 minutes and thenstirred at 45° C. for 2 hours. The reaction mixture was concentrated invacuo. The resulting residue was chromatographed on silica gel (500 ml)eluting with a mixture of n-hexane and ethyl acetate (6:1 v/v). Thefractions containing the desired compound were collected and evaporatedunder reduced pressure to give4-(6-bromohexylthio)-N-t-butyloxycarbonylpiperidine (4.95 g).

NMR (CDCl₃, δ): 1.45 (9H, s), 1.45-1.70 (8H, m), 1.80-2.00 (4H, m), 2.55(1H, t, J=7.34 Hz), 2.65-3.05 (3H, m), 3.30-3.50 (2H, m), 3.85-4.10 (2H,m).

APCI MASS (m/z): 250 (M⁺−101).

PREPARATION 123

To a solution of 4-(6-bromohexylthio)-N-t-butyloxycarbonylpiperidine(4.95 g) in methanol (20 ml) was added 28% sodium methoxide methanolsolution (26.6 ml), and the mixture was stirred under reflux for 4hours. After cooling, the reaction mixture was evaporated in vacuo. Theresulting residue was chromatographed on silica gel (400 ml) elutingwith a mixture of n-hexane and ethyl acetate (5:1 v/v). The fractionscontaining the object compound were collected and evaporated underreduced pressure to give4-(6-methoxyhexylthio)-N-t-butyloxycarbonylpiperidine (3.32 g).

NMR (CDCl₃, δ): 1.25-1.45 (6H, m), 1.45 (9H, s), 1.45-1.60 (4H, m),1.80-2.00 (2H, m), 2.54 (2H, t, J=7.47 Hz), 2.60-3.00 (3H, m), 3.30 (3H,s), 3.37 (2H, t, J=6.34 Hz), 3.96 (2H, m).

PREPARATION 124

To a solution of 4-(6-methoxyhexylthio)-N-t-butoxycarbonylpiperidine(3.32 g) in dichloromethane (40 ml) were added triethylsilane (8.0 ml)and trifluoroacetic acid (15.4 ml) with stirring in an ice bath. Themixture was stirred at ambient temperature for 2 hours. The reactionmixture was evaporated in vacuo. The resulting residue waschromatographed on silica gel (400 ml) eluting with a mixture ofdichloromethane and methanol (4:1 v/v). The fractions containing theobject compound were collected and evaporated under reduced pressure togive 4-(6-methoxyhexylthio)piperidine (4.77 g). This compound wasimmediately used as the starting compound for the next step.

NMR (CD₃OD, δ): 1.30-1.90 (10H, m), 2.10-2.30 (2H, m), 2.60 (2H, t,J=7.30 Hz), 3.31 (3H, s), 3.42 (2H, t, J=4.28 Hz).

APCI MASS (m/z): 232.4 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 98.

PREPARATION 125 4-(6-Methoxyhexylthiopiperidin-1-yl)benzonitrile

NMR (CDCl₃, δ): 1.30-1.50 (4H, m), 1.50-1.80 (6H, m), 1.95-2.15 (2H, m),2.57 (2H, t, J=7.50 Hz), 2.75-3.10 (3H, m), 3.33 (3H, s), 3.37 (2H, t,J=6.32 Hz), 3.65-3.90 (2H, m), 6.84 (2H, d, J=9.08 Hz), 7.47 (2H, d,J=9.08 Hz).

APCI MASS (m/z): 347 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 99.

PREPARATION 1262-Amino-5-[4-[4-(6-methoxyhexylthio)piperidin-1-yl]phenyl]-1,3,4-thiadiazole

NMR (DMSO-d₆, δ): 1.20-1.60 (10H, m), 1.85-2.05 (2H, m), 2.45-2.60 (2H,m), 2.80-3.00 (3H, m), 3.21 (3H, s), 3.29 (2H, t, J=6.42 Hz), 3.60-3.80(2H, m), 6.97 (2H, d, J=8.94 Hz), 7.20 (2H, s), 7.55 (2H, d, J=8.80 Hz).

APCI MASS (m/z): 421 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 100.

PREPARATION 1274-[2-[4-[4-(6-Methoxyhexylthio)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid ethyl ester trifluroacetic acid salt

ESI MASS (m/z) (Positive): 579 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 101.

PREPARATION 1284-[2-[4-[4-(6-Methoxyhexylthio)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]bezoicacid

NMR (CDCl₃, δ): 1.30-1.80 (10H, m), 1.95-2.25 (2H, m), 2.45-2.70 (2H,m), 2.70-3.20 (4H, m), 3.35 (3H, s), 3.35-3.50 (2H, m), 6.80-7.05 (3H,m), 7.36 (1H, s), 7.63 (1H, d, J=8.19 Hz), 7.75 (1H, d, J=8.21 Hz), 7.89(1H, d, J=7.52 Hz), 8.00-8.20 (2H, m).

APCI MASS (m/z): 551 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 102.

PREPARATION 1294-[2-[4-[4-(6-Methoxyhexylthio)piperidin-1-yl]phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1772, 1603, 1535, 1470 cm⁻¹.

PREPARATION 130

To a solution of tetrahydrothiopyran-4-one (1.0 g) in dichloromethane(20 ml) was added 3-chloroperoxybenzoic acid (4.16 g, purity 80%) underice-cooling with stirring. The mixture was stirred at the sametemperature for 20 minutes and then stirred at ambient temperature for 1hour. The resulting precipitates were filtered off, and the filtrate wasconcentrated in vacuo. The residue was dissolved in a mixture of ethylacetate. (50 ml) and water (20 ml) and adjusted to pH 2 with1N-hydrochloric acid. The organic layer was separated, and the aqueouslayer was extracted with ethyl acetate (50 ml). The organic layers werecombined, washed in turn with water, saturated aqueous sodiumbicarbonate and saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and evaporated in vacuo. The resulting residue wasdissolved in a mixture of dichloromethane (100 ml) and methanol (20 ml),dried over anhydrous magnesium sulfate and evaporated in vacuo to give1,1-dioxotetrahydrothiopyran-4-one (1.18 g).

NMR (CD₃CD, δ): 2.20 (4H, t, J=6.05 Hz), 2.90-3.20 (4H, m).

PREPARATION 131

To a solution of (R,S)-5-hydroxy-2-phenyl-1,3-dioxane (5.0 g) (ActaChemica Scandinavia, 1996; 50: 185-187) in DMF (50 ml) were addedt-butyl dimethylsilyl chloride (12.5 g) and imidazole (9.45 g) withstirring at ambient temperature, and the mixture was allowed to stand atthe same temperature overnight. The reaction mixture was poured into pH6.86 standard buffer solution (500 ml) and extracted twice with ethylacetate (200 ml). The extracts were combined, washed successively withwater and saturated aqueous sodium chloride, dried over anhydrousmagnesium sulfate and evaporated in vacuo. The resulting residue waschromatographed on silica gel (400 ml) eluting with a mixture ofn-hexane and ethyl acetate (9:1 v/v). The fractions containing theobject compound were collected and evaporated under reduced pressure togive (R,S)-5-(tert-butyldimethylsilyloxy)-2-phenyl-1,3-dioxane (10.14g).

NMR (CDCl₃, δ): 0.02-0.12 (6H, m), 0.89-0.94 (9H, m), 3.50-4.25 (5H, m),5.50-5.95 (1H, m), 7.30-7.55 (5H, m).

ESI MASS (m/z) (Positive): 317.3 (M⁺+Na).

PREPARATION 132

A solution of (R,S)-5-tert-butyldimethylsilyloxy-2-phenyl-1,3-dioxane(10.1 g) and 10% palladium on carbon (50% including water) (5.0 g) inmethanol (100 ml) was hydrogenated under an atmospheric pressure ofhydrogen with stirring at ambient temperature for 2 hours. The catalystwas filtered off, and the filtrate was dried over anhydrous magnesiumsulfate and evaporated in vacuo. The resulting residue waschromatographed on silica gel (300 ml), eluting with a mixture ofn-hexane and ethyl acetate (3:1 v/v). The fractions containing theobject compound were collected and evaporated under reduced pressure togive (R,S)-2-(tert-butyldimethylsilyloxy)-3-hydroxypropanol (5.69 g).This compound was immediately used as the starting compound for the nextstep. To a solution of this compound were successively addeddiisopropylethylamine (14.4 ml) and acetyl chloride (6.5 ml) withstirring, and the mixture was stirred at 0-5° C. for 2 hours water (10ml) was added to the reaction mixture, and the organic layer wasseparated, washed with saturated aqueous sodium chloride, dried overanhydrous magnesium sulfate and evaporated in vacuo. The resultingresidue was dissolved in a mixture of methanol (100 ml) and conc.hydrochloric acid (1.0 ml), and the solution was stirred at ambienttemperature for 2 hours. The reaction mixture was concentrated in vacuoand chromatographed on silica gel (200 ml) eluting with a mixture ofn-hexane and ethyl acetate (2:1 v/v). The fractions containing theobject compound were collected and evaporated under reduced pressure togive (R,S)-2-hydroxy-1,3-diacetoxypropane (2.06 g).

NMR (CDCl₃, δ): 2.06 (3H, s), 2.11 (3H, s), 3.74 (1H, m), 4.10-4.25 (4H,m).

PREPARATION 133

To a solution of oxalyl chloride (1.09 ml) in dichloromethane (20 ml wasadded dropwise dimethylsulfoxide (DMSO) (1.93 ml) with stirring at−40-50° C. After stirring at the same temperature for 5 minutes, to thesolution was added dropwise a solution of(R,S)-2-hydroxy-1,3-diacetoxypropane (2.0 g) in dichloromethane (20 ml)and stirred at the same temperature for 30 minutes. Triethylamine (5.54ml) was added dropwise to the reaction mixture with stirring at the sametemperature, and then the mixture was stirred at ambient temperature for30 minutes. The insoluble material was filtered off, and the filtratewas washed successively with 0.5N hydrochloric acid, water, saturatedaqueous sodium bicarbonate and saturated aqueous sodium chloride, driedover anhydrous magnesium sulfate and evaporated in vacuo. The resultingresidue was chromatographed on silica gel (200 ml) eluting with amixture of n-hexane and ethyl acetate (1:2 v/v). The fractionscontaining the object compound were collected and evaporated underreduced pressure to give 2-oxo-1,3-diacetoxypropane (1.17 g).

NMR (CDCl₃, δ): 2.18 (6H, s), 4.76 (4H, s).

ESI MASS (m/z) (Positive): 197.3 (M⁺+Na).

PREPARATION 134

To a solution of (R,S)-5-hydroxy-2-phenyl-1,3-dioxane (10.0 g) (ActaChemica Scandinavica, 1996; 50: 185-187) in dichloromethane (200 ml)were added molecular sieves 4A powder (28 g) and pyridiniumchlorochromic acid (PCC) (23.9 g) with stirring at ambient temperatureand the mixture was stirred at the same temperature for 2 hours. To thereaction mixture was added diethyl ether (100 ml), and the insolublematerial was filtered off with celite and the filtrates were evaporatedin vacuo. The residue was dissolved in a mixture of n-hexane (100 ml)and ethyl acetate (100 ml), dried over anhydrous magnesium sulfate andevaporated in vacuo. The resulting residue was chromatographed on silicagel (600 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1v/v). The fractions containing the object compound were collected andevaporated under reduced pressure to give 5-oxo-2-phenyl-1,3-dioxane(7.06 g).

NMR (CDCl₃, δ): 4.49 (2H, s), 4.50 (2H, s), 5.90 (1H, s), 7.30-7.60 (5H,m).

PREPARATION 135

To a solution of 4-aminobutanol (630 mg), 5-oxo-2,2-dimethyl-1,3-dioxane(1.0 g) and acetic acid (1.20 ml) in MeOH (9 ml)-DMF (4 ml) was addedsodium cyanoborohydride (622 mg) with stirring at ambient temperature,and the mixture was stirred at the same temperature overnight. To thereaction mixture was added dropwise a solution of allyloxycarbonylchloride (0.97 ml) in THF (2 ml) with stirring under ice-cooling, andthe mixture was stirred at the same temperature for 1 hour. To thereaction mixture were added ethyl acetate (50 ml) and n-hexane (10 ml),and the solution was washed in turn with water and saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and evaporatedin vacuo. The resulting residue was chromatographed on silica gel (100ml) eluting with a mixture of n-hexane and ethyl acetate (1:1 v/v). Thefractions containing the object compound were collected and evaporatedunder reduced pressure to give4-[allyloxycarbonyl-(2,2-dimethyl-1,3-dioxan-5-yl)]aminobutanol (1.04g).

NMR (CDCl₃, δ): 1.42 (3H, s), 1.48 (3H, s), 1.50-1.80 (4H, m), 3.45 (2H,t, J=8.20 Hz), 3.68 (2H, ABq, J=5.84 and 11.36 Hz), 3.80-4.20 (5H, m),4.50-4.70 (2H, m), 5.15-5.40 (2H, m), 5.80-6.05 (1H, m).

ESI MASS (m/z) (Positive): 310.3 (M⁺+Na).

PREPARATION 136

To a solution of oxalyl chloride (0.32 ml) in dichloromethane (10 ml)was added DMSO (0.57 ml) dropwise with stirring at −40-50° C. Afterstirring at the same temperature for 5 minutes, to the solution wasadded dropwise a solution of4-[allyloxycarbonyl(2,2-dimethyl-1,3-dioxan-5-yl)]aminobutanol (1.0 g)in dichloromethane (5 ml) and stirred at the same temperature for 30minutes. Triethylamine (1.46 ml) was added dropwise to the reactionmixture with stirring at the same temperature, and then the mixture wasstirred at ambient temperature for 30 minutes. The insoluble materialwas filtered off, and the filtrate was washed successively with1N-hydrochloric acid, water, saturated aqueous sodium bicarbonate andsaturated aqueous sodium chloride, dried over anhydrous magnesiumsulfate and evaporated in vacuo. The resulting residue was dissolved ina mixture of acetic acid (16 ml) and water (4 ml), and the solution wasstirred at 90-100° C. for 5 hours. The reaction mixture was concentratedin vacuo. The resulting residue was chromatographed on silica gel (100ml) eluting with a mixture of dichloromethane and methanol (19:1 v/v).The fractions containing the object compound were collected andevaporated under reduced pressure to give4-[allyloxycarbonyl-(1,3-dihydropropan-2-yl)]aminobutylaldehyde (321mg).

NMR (CDCl₃, δ): 1.50-1.75 (2H, m), 1.80-2.00 (2H, m), 2.40-2.60 (2H, m),3.20-4.10 (7H, m), 4.59 (2H, d, J=5.60 Hz), 5.10-5.40 (2H, m), 5.80-6.10(1H, m).

APCI MASS (m/z) (Positive): 246 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 95.

PREPARATION 137 N-t-Butoxycarbonyl-4-allyloxypiperidine

NMR (CDCl₃, δ): 1.45 (9H, s), 1.45-1.60 (2H, m), 1.70-1.95 (2H, m),3.00-3.20 (2H, m), 3.40-3.60 (1H, m), 3.65-3.90 (2H, m), 3.95-4.05 (2H,m), 5.10-5.35 (2H, m), 5.80-6.10 (1H, m).

PREPARATION 138

To a solution of N-t-butoxycarbonyl-4-allyloxypiperidine (2.95 g) in THF(15 ml) was added 9-borobicyclo[3.3.1]nonane (9-BBN, 0.5M solution inTHF) (51.3 ml) under ice-cooling with stirring, and the mixture wasstirred at ambient temperature for 4 hours. The reaction mixture wascooled at 0-5° C., and 3M aqueous sodium hydroxide (20.4 ml) and 30%hydrogen peroxide aqueous solution (20.4 ml) were added the reactionmixture at 0-5° C. The mixture was stirred at ambient temperature for 1hour. To a reaction mixture was added ethyl acetate (100 ml), and thesolution was washed successively with saturated aqueous sodium chloride,1N-hydrochloric acid, saturated aqueous sodium bicarbonate and saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate andevaporated in vacuo. The resulting residue was chromatographed on silicagel (200 ml) eluting with a mixture of dichloromethane and methanol (9:1v/v). The fractions containing the desired compound were collected andevaporated under reduced pressure to give4-(3-hydroxypropyloxy)-N-t-butoxycarbonylpiperidine (3.83 g).

NMR (CDCl₃, δ): 1.43 (9H, s), 1.43-1.60 (2H, m), 1.70-1.90 (4H, m),2.35-2.45 (1H, m), 3.00-3.20 (2H, m), 3.35-3.55 (1H, m), 3.60-3.90 (5H,m).

PREPARATION 139

To a solution of 4-(3-hydroxypropyloxy)-N-t-butyloxycarbonylpiperidine(3.82 g) in ethyl acetate (40 ml) were added triethylamine (4.1 ml) andmethanesulfonyl chloride (1.37 ml) with stirring under ice-cooling, andthe mixture was stirred at the same temperature for 1 hour. To thereaction mixture were added water (50 ml) and ethyl acetate (50 ml) withstirring. The organic layer was separated, washed twice with saturatedaqueous sodium chloride, dried over anhydrous magnesium sulfate andevaporated in vacuo. The resulting residue was chromatographed on silicagel (150 ml) eluting with a mixture of n-hexane and ethyl acetate (1:1v/v). The fractions containing the desired compound were collected andevaporated under reduced pressure to give4-[3-(methanesulfonyloxy)propyloxy]-N-t-butyloxycarbonylpiperidine (3.77g).

NMR (CDCl₃, δ): 1.45 (9H, s), 1.45-1.60 (2H, m), 1.70-1.90 (2H, m),1.90-2.10 (2H, m), 3.01 (3H, s), 3.03-3.20 (2H, m), 3.30-3.50 (1H, m),3.57 (2H, t, J=5.87 Hz), 3.65-3.80 (2H, m), 4.35 (2H, t, J=6.18 Hz).

ESI MASS (m/z) (Positive): 360.3 (M⁺+Na).

PREPARATION 140

To a solution of4-[3-(methanesulfonyloxy)propyloxy]-N-t-butyloxycarbonylpiperidine (3.76g) in methanol (20 ml) was added 28% sodium methoxide methanol solution(22.7 ml), and the mixture was stirred under refluxing for 1.5 hours.The reaction mixture was evaporated in vacuo and dissolved in ethylacetate (200 ml). The solution was washed twice with saturated aqueoussodium chloride, dried over anhydrous magnesium sulfate and evaporatedin vacuo. The resulting residue was chromatographed on silica gel (200ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). Thefractions containing the object compound were collected and evaporatedunder reduced pressure to give4-(3-methoxypropyloxy)-N-t-butyloxycarbonylpiperidine (2.66 g).

NMR (CDCl₃, δ): 1.45 (9H, s), 1.45-1.60 (2H, m), 1.70-1.90 (4H, m),3.00-3.15 (2H, m), 3.33 (3H, s), 3.35-3.60 (5H, m), 3.65-3.85 (2H, m).

ELSI MASS (m/z): 296.3 (M⁺+Na).

PREPARATION 141

A mixture of 1-acetyl-4-(4-hydroxyphenyl)piperazine (5.00 g) inN,N-dimethylformamide (50 ml) was treated with 1,6-dibromohexane (10.5ml) and potassium carbonate (4.71 g), and the mixture was stirred for 18hours at ambient temperature. To the reaction mixture was added water(200 ml), and the resulting precipitate was collected by filtration,washed with water and n-hexane successively and dried under reducedpressure to give crude 1-acetyl-4-[4-(6-bromohexyloxy)phenyl]piperazine(10.52 g), that was used in the next reaction directly.

MASS (m/z): 383 (M⁺+1).

PREPARATION 142

A solution of crude 1-acetyl-4-[4-(6-bromohexyloxy)phenyl]piperazine(10.52 g) in methanol (105 ml) was treated with 28% sodium methoxide inmethanol (105 ml), and the solution was refluxed for 7 hours. Aftercooling, the precipitate was removed by filtration. The filtrate wasadded to a mixture of methylene chloride and water. The organic layerwas taken, dried over magnesium sulfate, filtered and evaporated to givea crude oil. This oil in methylene chloride (20 ml) was treated withacetic anhydride (6.4 ml) under ice-cooling. After 6 hours, the solutionwas added to a mixture of methylene chloride and water. The organiclayer was taken, dried over magnesium sulfate, filtered and evaporated.The residue was purified by silica gel column chromatography elutingwith a mixed solvent of methylene chloride-methanol (from 0% to 3%gradient elution) to give1-acetyl-4-[4-(6-methoxyhexyloxy)phenyl]piperazine (5.38 g) as a palered solid.

NMR (DMSO-d₆, δ): 1.24-1.78 (8H, m), 2.03 (3H, s), 2.86-3.06 (4H, m),3.21 (3H, s), 3.23-3.36 (2H, m), 3.48-3.65 (4H, m), 3.87 (2H, d, J=6.4Hz), 6.82 (2H, dd, J=9.2 and 2.6 Hz), 6.88 (2H, dd, J=9.3 and 2.6 Hz).

MASS (m/z): 335 (M⁺+1).

PREPARATION 143

A mixture of 1-acetyl-4-[4-(6-methoxyhexyloxy)phenyl]piperazine (4.87 g)and 6N-hydrochloric acid (50 ml) was heated at 75° C. for 3 hours. Aftercooling, the solution was adjusted to pH 11 with 25% sodium hydroxideaqueous solution then the resulting precipitate was collected byfiltration, washed with water and dried under reduced pressure to give4-[4-(6-methoxyhexyloxy)phenyl]piperazine (3.77 g) as a pale brownsolid.

NMR (DMSO-d₆, δ): 1.25-1.78 (8H, m), 2.74-2.96 (8H, m), 3.21 (3H, s),3.30 (2H, t, J=6.3 Hz), 3.86 (2H, t, J=6.4 Hz), 6.79 (2H, d, J=9.2 Hz),6.83 (2H, d, J=9.5 Hz).

MASS (m/z): 293 (M⁺+1).

PREPARATION 144

A mixture of ethyl 4-fluorobenzoate (1.90 g) and1-[4-(6-methoxyhexyloxy)phenyl]piperazine (3.00 g) in dimethylsulfoxide(45 ml) was treated with potassium carbonate (4.25 g), and the mixturewas heated at 150° C. for 22 hours. After cooling, water (200 ml) wasadded to the reaction mixture, and the resulting precipitate wascollected by filtration, washed with water and dried under reducedpressure at 50° C. for 7 hours to give ethyl4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoate (3.20 g) as anocher solid.

NMR (DMSO-d₆, δ): 1.22-1.79 (8H, m), 1.33 (3H, t, J=7.1 Hz), 3.08-3.20(4H, m), 3.21 (3H, s), 3.27-3.40 (2H, m), 3.40-3.54 (4H, m), 3.68 (2H,t, J=6.4 Hz), 4.24 (2H, q, J=7.1 Hz), 6.83 (2H, d, J=9.0 Hz), 6.94 (2H,d, J=9.1 Hz), 7.04 (2H, d, J=9.0 Hz), 7.81 (2H, d, J=8.9 Hz).

MASS (m/z): 441 (M⁺+1).

PREPARATION 145

A mixture of ethyl4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoate (3.00 g) inethanol (30 ml) was treated with 1N-sodium hydroxide aqueous solution(6.81 ml) then the mixture was refluxed for 24 hours, during whichperiod tetrahydrofuran (20 ml) and 1N-sodium hydroxide aqueous solution(6.81 ml) was added. After cooling, water was added to the mixture, andthe acidity of the mixture was adjusted to pH 1 with 1N-hydrochloricacid. The resulting precipitate was filtered, washed with water anddried under reduced pressure to give4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoic aciddihydrochloride (2.25 g) as an ocher solid.

NMR (DMSO-d₆, δ): 1.24-1.78 (8H, m), 3.04-3.21 (4H, m), 3.21 (3H, s),3.30 (2H, t, J=6.3 Hz), 3.34-3.56 (4H, m), 3.88 (2H, t, J=6.4 Hz), 6.83(2H, d, J=9.2 Hz), 6.94 (2H, d, J=9.2 Hz), 7.01 (2H, d, J=9.0 Hz), 7.79(2H, d, J=8.8 Hz).

MASS (m/z): 413 (M⁺+1).

PREPARATION 146

A mixture of 4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoicacid dihydrochloride (2.00 g) and 1-hydroxybenzotriazole (0.84 g) inmethylene chloride (40 ml) was treated with triethylamine (1.44 ml) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, and themixture was stirred for 24 hours at ambient temperature. The reactionmixture was added to water. The organic layer was taken, washed withsaturated sodium hydrogen carbonate aqueous solution, water andsaturated sodium chloride aqueous solution successively, and dried overmagnesium sulfate. Magnesium sulfate was filtered off, and the filtratewas evaporated under reduced pressure. To the residue was addeddiisopropyl ether, and the resulting precipitate was filtered, washedwith diisopropyl ether and dried under reduced pressure to give4-[4-(4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoic acidbenzotriazol-1-yl ester (2.30 g) as a dark yellow solid.

NMR (CDCl₃, δ): 1.33-1.87 (8H, m), 3.15-3.28 (4H, m), 3.34 (3H, s), 3.39(2H, t, J=6.4 Hz), 3.54-3.67 (4H, m), 3.93 (2H, t, J=6.5 Hz), 6.87 (2H,d, J=9.3 Hz), 6.95 (2H, d, J=9.3 Hz), 7.00 (2H, d, J=9.1 Hz), 7.37-7.58(3H, m), 8.10 (1H, d, J=8.2 Hz), 8.15 (2H, d, J=9.1 Hz).

MASS (m/z): 530 (M⁺+1).

PREPARATION 147

A mixture of 1-acetyl-4-(4-hydroxyphenyl)piperazine (3.00 g) inN,N-dimethylformamide was treated with 3-bromo-1-propanol (1.60 ml) andpotassium carbonate (2.82 g), and the mixture was heated at 60° C. for 8hours. Then 3-bromo-1-propanol (1.60 ml) was added again, and themixture was heated at 110° C. for 6 hours. After cooling, water andmethylene chloride were added to the reaction mixture, and the organiclayer was taken and dried over magnesium sulfate. Magnesium sulfate wasfiltered off, and the filtrate was evaporated under reduced pressure.The residue was purified by silica gel chromatography eluting with amixed solvent of methylene chloride-methanol (from 0% to 6% gradientelution) to give 1-acetyl-4-[4-(3-hydroxypropyloxy)phenyl]piperazine(3.53 g) as a pale pink solid.

NMR (DMSO-d₆, δ): 1.82 (2H, t, J=6.3 Hz), 2.03 (3H, s), 2.84-3.06 (4H,m), 3.45-3.62 (4H, m), 3.95 (2H, t, J=6.4 Hz), 4.13 (2H, t, J=6.5 Hz),4.47-4.60 (1H, m), 6.82 (2H, d, J=9.2 Hz), 6.90 (2H, d, J=9.3 Hz).

MASS (m/z): 279 (M⁺+1).

PREPARATION 148

A solution of 1-acetyl-4-[4-(3-hydroxypropyloxy)phenyl]piperazine (3.47g) in a mixed solvent of tetrahydrofuran (35 ml) andN,N-dimethylformamide (10 ml) was treated with silver(I) oxide (3.18 g)and 3-bromocyclohexene (1.86 ml), and the mixture was stirred at ambienttemperature for 16 hours. To the mixture was added silver(I) oxide (3.18g) and 3-bromocyclohexene (1.86 ml) again, and the mixture was heated at60° C. for 3 hours and then at 110° C. for 40 hours. The precipitate wasremoved by filtration, and the filtrate was evaporated. The residue waspurified by silica gel column chromatography eluting with a mixedsolvent of methylene chloride-methanol (from 0% to 5% gradient solution)to give crude1-acetyl-4-[4-[3-(2-cyclohexen-1-yloxy)propyloxy]phenylpiperazine (1.60g), that was used in the next reaction directly.

MASS (m/z): 359 (M⁺+1).

PREPARATION 149

A mixture of crude1-acetyl-4-[4-[3-(2-cyclohexen-1-yloxy)propyloxy]phenyl]piperazine (1.55g) in ethanol (16 ml) was hydrogenated at atmospheric pressure with 10%palladium-carbon (0.16 g) for 5 hours. After removal of catalyst byfiltration, the filtrate was concentrated in vacuo to give crude1-acetyl-4-[4-(3-cyclohexyloxypropyloxy)phenyl]piperazine (1.18 g), thatwas used in the next reaction directly, as a brown oil.

MASS (m/z): 361 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 143.

PREPARATION 150 4-[4-(3-Cyclohexyloxypropyloxy)phenyl]piperazine

NMR (CDCl₃, δ): 1.12-1.94 (10H, m), 1.94-2.11 (2H, m), 3.03 (8H, s),3.57-3.68 (1H, m), 3.86 (2H, t, J=5.9 Hz), 4.09 (2H, t, J=5.9 Hz), 6.86(2H, d, J=9.0 Hz), 6.89 (2H, d, J=9.0 Hz).

APCI MASS (m/z): 319 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 144.

PREPARATION 151

Ethyl 4-[4-[4-(3-cyclohexyloxypropyloxy)phenyl]piperazin-1-yl]benzoate

NMR (CDCl₃, δ): 1.12-1.95 (10H, m), 1.38 (3H, t, J=7.1 Hz), 1.95-2.14(2H, m), 3.13-3.30 (4H, m), 3.42-3.56 (4H, m), 3.61 (2H, t, J=6.2 Hz),3.81-3.94 (1H, m), 4.10 (2H, t, J=5.9 Hz), 4.34 (2H, q, J=7.1 Hz),6.78-7.01 (6H, m), 7.95 (2H, d, J=8.9 Hz).

MASS (m/z): 467 (M⁺+1).

PREPARATION 152

A mixture of ethyl4-[4-[4-(3-cyclohexyloxypropyloxy)phenyl]piperazin-1-yl]benzoate (290mg) in the mixed solvent of tetrahydrofuran (15 ml) and ethanol (3 ml)was treated with 10% sodium hydroxide aqueous solution (0.50 ml), andthe mixture was refluxed for 8 hours. After cooling, water was added tothe reaction mixture, and the acidity of the mixture was adjusted to pH1 with 1N-hydrochloric acid. The resulting precipitate was filtered,washed with water and dried under reduced pressure to give4-[4-[4-(3-cyclohexyloxypropyloxy)phenyl]piperazin-1-yl]benzoic aciddihydrochloride (96 mg) as a pale brown solid.

NMR (DMSO-d₆, δ): 1.08-1.96 (12H, m), 3.07-3.62 (11H, m), 3.95 (2H, t,J=5.5 Hz), 6.84 (2H, d, J=9.1 Hz), 6.94 (2H, d, J=9.2 Hz), 7.03 (2H, d,J=8.9 Hz), 7.79 (2H, d, J=8.7 Hz).

MASS (m/z): 439 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 146.

PREPARATION 1534-[4-[4-(3-Cyclohexyloxypropyloxy)phenyl]piperazin-1-yl]benzoic acidbenzotriazol-1-yl ester

MASS (m/z): 556 (M⁺+1).

PREPARATION 154

A solution of 4-bromo-2,6-dimethylphenol (2.00 g) and 1,7-dibromoheptane(5.10 g) in N,N-dimethylformamide (20 ml) was treated with potassiumcarbonate (2.06 g), and the mixture was stirred for 5 hours at ambienttemperature. To the reaction mixture was added water and methylenechloride, and the organic layer was separated and dried over magnesiumsulfate. Magnesium sulfate was filtered off, and the filtrate wasconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting successively with the following solvents: (1)n-hexane, (2) n-hexane:ethyl acetate=4:1, (3) n-hexane:ethylacetate=1:1. The fractions containing the object compound wereconcentrated in vacuo to give crude5-bromo-2-(7-bromoheptyloxy)-1,3-dimethylbenzene, that was used in thenext reaction directly, as a pale yellow oil.

NMR (CDCl₃, δ): 1.28-1.98 (10H, m), 2.23 (6H, s), 3.35-3.50 (2H, m),3.71 (2H, t, J=6.4 Hz), 7.13 (2H, s).

PREPARATION 155

A solution of crude 5-bromo-2-(7-bromoheptyloxy)-1,3-dimethylbenzene(7.81 g) in methanol (78 ml) was treated with 28% sodium methoxide inmethanol (78 ml), and the solution was refluxed for 8 hours. Aftercooling, the reaction mixture was evaporated under reduced pressure, andthe residue was extracted with methylene chloride. The organic layer wasdried over magnesium sulfate and magnesium sulfate was filtered off, andthen the filtrate was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography eluting with a mixedsolvent of n-hexane-ethyl acetate (from 0% to 7% gradient elution) togive 5-bromo-2-(7-methoxyheptyloxy)-1,3-dimethylbenzene (3.34 g) as acolorless oil.

NMR (CDCl₃, δ): 1.38-1.69 (8H, m), 1.69-1.89 (2H, m), 2.23 (6H, s), 3.35(3H, s), 3.28-3.44 (2H, m), 3.65-3.78 (2H, m), 7.13 (2H, s).

MASS (m/z): 329 (M⁺+1).

PREPARATION 156

To a mixture of cesium carbonate (1.39 g), palladium(II) acetate (34.1mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (142 mg) in toluene(3.1 ml) was successively added ethyl 4-(piperazin-1-yl)benzoate (0.85g) and a solution of 5-bromo-2-(7-methoxyheptyloxy)-1,3-dimethylbenzene(1.00 g) in toluene (3 ml) in a stream of nitrogen. The mixture wasstirred at ambient temperature for 30 minutes and refluxed for a further20 hours. After cooling, the reaction mixture was concentrated in vacuoand to the residue was added water and methylene chloride. The organiclayer was separated, washed with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting successively with the following solvent: (1) n-hexane, (2)n-hexane;ethyl acetate=9:1, (3) n-hexane:ethyl acetate=5:1. Thefractions containing the object compound were concentrated in vacuo togive ethyl4-[4-[4-(7-methoxyheptyloxy)-3,5-dimethylphenyl]piperazin-1-yl]benzoate(0.53 g) as a pale yellow solid.

NMR (CDCl₃, δ): 1.32-1.69 (11H, m), 1.69-1.88 (2H, m), 2.26 (6H, s),3.17-3.30 (4H, m), 3.33 (3H, s), 3.38 (2H, t, J=6.5 Hz), 3.41-3.54 (4H,m), 3.71 (2H, t, J=6.5 Hz), 4.34 (2H, q, J=7.1 Hz), 6.63 (2H, s), 6.91(2H, d, J=9.0 Hz), 7.95 (2H, d, J=9.0 Hz).

MASS (m/z): 483 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 152.

PREPARATION 1574-[4-[4-(7-Methoxyheptyloxy)-3,5-dimethylphenyl]piperazin-1-yl]benzoicacid dihydrochloride

NMR (DMSO-d₆, δ): 1.22-1.60 (8H, m), 1.60-1.79 (2H, m), 2.17 (6H, s),3.10-3.50 (10H, m), 3.21 (3H, s), 3.64 (2H, t, J=6.3 Hz), 6.65 (2H, s),7.01 (2H, d, J=9.0 Hz), 7.79 (2H, d, J=8.8 Hz), 12.30 (1H, br s).

MASS (m/z): 455 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 146.

PREPARATION 1584-[4-[4-(7-Methoxyheptyloxy)-3,5-dimethylphenyl]piperazin-1-yl]benzoicacid benzotriazol-1-yl ester

NMR (CDCl₃, δ): 1.32-1.89 (10H, m), 2.27 (6H, s), 3.20-3.34 (4H, m),3.34 (3H, s), 3.38 (2H, t, J=6.5 Hz), 3.54-3.68 (4H, m), 3.72 (2H, t,J=6.5 Hz), 6.64 (2H, s), 7.00 (2H, d, J=9.1 Hz), 7.37-7.62 (3H, m), 8.09(2H, d, J=8.3 Hz), 8.15 (2H, d, J=9.0 Hz). MASS (m/z): 572 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 152.

PREPARATION 159 4-[4-(4-Cyclohexylpiperazin-1-yl)phenyl]benzoic aciddihydrochloride

NMR (DMSO-d₆, δ): 1.03-2.19 (10H, m), 2.80-2.93 (1H, m), 3.10-3.49 (8H,m), 7.08 (2H, d, J=8.4 Hz), 7.65 (2H, d, J=8.6 Hz), 7.75 (2H, d, J=8.4Hz), 7.97 (2H, d, J=8.3 Hz).

MASS (m/z): 365 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 146.

PREPARATION 160 4-[4-(4-Cyclohexylpiperazin-1-yl)phenyl]benzoic acidbenzotriazol-1-yl ester

NMR (CDCl₃, δ): 1.04-1.43 (6H, m), 1.69-2.04 (4H, m), 2.24-2.47 (1H, s),2.68-2.88 (4H, m), 3.20-3.43 (4H, m), 7.03 (2H, d, J=8.8 Hz), 7.38-7.66(3H, m), 7.63 (2H, d, J=8.7 Hz), 7.79 (2H, d, J=8.5 Hz), 8.12 (1H, d,J=8.2 Hz), 8.30 (2H, d, J=8.5 Hz).

MASS (m/z): 482 (M⁺+1).

PREPARATION 161

To a solution of methyl 4-(4-hydroxyphenyl)benzoate (0.94 g),(S)-(−)-2-(tert-butoxycarbonylamino)-3-cyclohexyl-1-propanol (1.00 g)and triphenylphosphine (1.62 g) in N,N-dimethylformamide (20 ml) wasadded dropwise diisopropyl azodicarboxylate (1.21 ml) for 10 minutesunder ice-cooling in a stream of nitrogen. The solution was stirred for16 hours at ambient temperature, and then water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated aqueous sodium chloridesolution, dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with a mixed solvent of n-hexane-ethyl acetate (from 0% to 20%gradient elution) to give methyl(S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoate(290 mg) as a white solid.

NMR (CDCl₃, δ): 1.72-1.93 (13H, m), 1.46 (9H, s), 3.90-4.16 (3H, m),3.93 (3H, s), 4.63-4.78 (1H, m), 6.93-7.05 (2H, m), 7.50-7.68 (4H, m),8.06-8.15 (2H, m).

MASS (m/z): 368 (M⁺+2−Boc).

PREPARATION 162

A solution of methyl(S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoate(0.28 g) in a mixed solvent of methanol (14 ml) and tetrahydrofuran (3ml) was treated with 1N-sodium hydroxide aqueous solution, and themixture was refluxed for 16 hours. After cooling, water was added to themixture, and the acidity of the mixture was adjusted to pH 1 with1N-hydrochloric acid. The resulting precipitate was filtered, washedwith water and dried under reduced pressure to give(S)-4-[4-[2-(tert-butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoicacid (222 mg) as a white solid.

NMR (DMSO-d₆, δ): 0.66-1.48 (8H, m), 1.39 (9H, s), 1.48-1.87 (5H, m),3.78-3.97 (3H, m), 6.79 (1H, d, J=7.2 Hz), 7.04 (2H, d, J=8.8 Hz), 7.68(2H, d, J=8.8 Hz), 7.75 (2H, d, J=8.4 Hz), 7.98 (2H, d, J=8.4 Hz), 12.83(1H, br s).

MASS (m/z): 354 (M⁺+2−Boc).

The following compound was obtained according to a similar manner tothat of Preparation 163.

PREPARATION 163(S)-4-[4-[2-(tert-Butoxycarbonylamino)-3-cyclohexylpropyloxy]phenyl]benzoicacid benzotriazol-1-yl ester

NMR (CDCl₃, δ): 0.75-1.96 (13H, m), 1.47 (9H, s), 3.92-4.20 (3H, m),4.60-4.79 (1H, m), 7.04 (2H, d, J=8.8 Hz), 7.40-7.63 (3H, m), 7.64 (2H,d, J=8.7 Hz), 7.79 (2H, d, J=8.4 Hz), 8.12 (1H, d, J=8.1 Hz), 8.32 (2H,d, J=8.4 Hz).

MASS (m/z): 571 (M⁺+1).

PREPARATION 164

A mixture of 1-fluoro-4-nitrobenzene (2.71 ml),1,2,3,6-tetrahydro-4-phenylpyridine hydrochloride (5 g) and potassiumcarbonate (8.83 g) in dimethylsulfoxide (50 ml) was stirred for 1 hourat 100° C. The reaction mixture was pulverized with water. Theprecipitate was collected by filtration, and dried under reducedpressure to give 4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)nitrobenzene.

IR (KBr): 1589.1, 1311.4, 1108.9 cm⁻¹.

NMR (CDCl₃, δ): 2.73-2.77 (2H, m), 3.73 (2H, t, J=11.3 Hz), 4.09 (2H,dd, J=2.5 and 5.9 Hz), 6.16-6.20 (1H, m), 6.80-6.88 (2H, m), 7.29-7.45(5H, m), 8.12-8.20 (2H, m).

MASS (m/z): 281 (M⁺+1).

PREPARATION 165

To a solution of 4-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)nitrobenzene(6.4 g) in ethyl alcohol (192 ml) and tetrahydrofuran (192 ml) was added10% palladium on carbon (0.64 g), and hydrogen gas at atmospherepressure for 6 hours. The reaction mixture was filtered through celiteand evaporated under reduced pressure to give1-(4-aminophenyl)-4-phenylpiperidine (5.66 g).

IR (KBr): 1604.5, 1511.9, 1382.7, 1207.2 cm⁻¹.

NMR (CDCl₃, δ): 1.84-1.97 (4H, m), 2.52-2.78 (3H, m), 3.10-3.73 (4H, m),6.63-6.70 (2H, m), 6.84-6.92 (2H, m), 7.17-7.37 (5H, m).

MASS (m/z): 253 (M⁺+1).

PREPARATION 166

To a solution of 1-(4-aminophenyl)-4-phenylpiperidine (2 g) in 47%hydrobromic acid (20 ml) and acetic acid (23 ml) was added dropwisesodium nitrite (0.55 g) in water (1 ml) under ice-cooling. The solutionwas then stirred for 30 minutes at 0° C. The reaction mixture was addeddropwise copper(I) bromide (2.27 g) in 47% hydrobromic acid (2.3 ml)under ice-cooling. The reaction mixture was then stirred for 1.5 hoursat ambient temperature. The reaction mixture was pulverized with water.The precipitate was collected by filtration. The powder was added1N-sodium hydroxide (21 ml) and extracted with ethyl acetate. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate. The magnesium sulfate was filtered off, and the filtrate wasevaporated under reduced pressure. The residue was purified by columnchromatography over silica using dichloromethane/n-hexane (1:1) as theelution to give 1-(4-bromophenyl)-4-phenylpiperidine (1.23 g).

IR (KBr): 1583.3, 1488.8, 1382.7, 1214.9 cm⁻¹.

NMR (CDCl₃, δ): 1.77-1.96 (4H, m), 2.57-2.71 (1H, m), 2.74-2.88 (2H, m),3.73-3.79 (2H, m), 6.81-6.89 (2H, m), 7.18-7.38 (7H, m).

MASS (m/z): 316 (M⁺+1).

PREPARATION 167

A mixture of piperazine-1-carboxylic acid tert-butyl ester (2.02 g),1-(4-bromophenyl)-4-phenylpiperidine (2.86 g),tris(dibenzylideneacetone)(chloroform)-di-palladium(0) (0.19 g),(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.28 g) and sodiumtert-butoxide (1.74 g) in toluene (29 ml) was stirred for 6 hours at 90°C. The reaction mixture was added to a mixture of water and ethylacetate. The organic layer was taken and dried over magnesium sulfate.The magnesium sulfate was filtered off, and the filtrate was evaporatedunder reduced pressure. The residue was purified by columnchromatography over silica using dichloromethane/methyl alcohol (50:1)as the elution to give4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine-1-carboxylic acidtert-butyl ester (2.93 g).

IR (KBr): 1691.3, 1596.8, 1116.6 cm⁻¹.

NMR (CDCl₃, δ): 1.48 (9H, s), 1.87-1.99 (4H, m), 2.60-2.90 (3H, m)3.00-3.16 (4H, m), 3.55-3.71 (6H, m), 6.87-6.99 (4H, m), 7.21-7.53 (5H,m).

MASS (m/z): 422 (M⁺+1).

PREPARATION 168

To a solution of4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine-1-carboxylic acidtert-butyl ester (2.45 g) in 1,4-dioxane (62 ml) was added dropwise4N-HCl/1,4-dioxane (58 ml) at ambient temperature. The reaction mixturewas stirred for 110 minutes at ambient temperature, and stirred for 2hours at 80° C. The precipitate was filtered and dried to give1-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine trihydrochloride salt(2.07 g).

IR (KBr): 3494.4, 3237.9, 1635.3, 1498.4 cm⁻¹.

NMR (DMSO-d₆, δ): 1.98-3.90 (18H, m), 7.02-7.41 (7H, m), 7.82-7.86 (2H,m).

MASS (m/z): 322.4 (M⁺+1) (free).

PREPARATION 169

A mixture of 4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazinetrihydrochloride salt (1.77 g) and 1N-sodium hydroxide (62 ml) indichloromethane (62 ml) was stirred for 30 minutes at ambienttemperature. The organic layer was separated, washed with brine, driedover magnesium sulfate. The magnesium sulfate was filtered off, and thefiltrate was evaporated under reduced pressure to give1-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine (1.19 g).

PREPARATION 170

A mixture of 4-fluorobenzoic acid ethyl ester (1.25 g),1-[4-(4-phenylpiperidin-1-yl)phenyl]piperazine (1.19 g) and potassiumcarbonate (1.53 g) in dimethylsulfoxide (18 ml) was stirred for 12 hoursat 150° C. The reaction mixture was pulverized with water. The mixturewas extracted with dichloromethane. The organic layer was separated,washed with brine, dried over magnesium sulfate. The magnesium sulfatewas filtered off, and the filtrate was evaporated under reducedpressure. The residue was purified by column chromatography over silicausing dichloromethane/methyl alcohol (200:1) as the elution. The powderwas recrystallized from toluene (60 ml). The crystal was collected byfiltration, and dried under reduced pressure to give4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acid ethylester (0.80 g).

IR (KBr): 1702.8, 1513.8, 1232.3 cm⁻¹.

NMR (CDCl₃, δ): 1.37 (3H, t, J=7.1 Hz), 1.89-2.00 (4H, m), 2.55-2.84(3H, m), 3.22-3.27 (4H, m), 3.46-3.51 (4H, m), 3.66-3.72 (2H, m), 4.34(2H, q, J=7.1 Hz), 6.90-7.03 (6H, m), 7.18-7.37 (5H, m), 7.93-7.98 (2H,m).

MASS (m/z): 470.

PREPARATION 171

To a mixture of4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]]benzoic acidethyl ester (0.78 g) in ethyl alcohol (39 ml) and 1,4-dioxane (39 ml)was added 10% NaOH aq. (1.3 ml) and refluxed for 16 hours. The reactionmixture was adjusted to pH 1-2 with 1N-HCl and the resulting precipitatewas collected by filtration, and dried under reduced pressure to give4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic aciddihydrochloride salt (0.65 g).

IR (KBr): 2840.6, 1670.1, 1602.6, 1232.3 cm⁻¹.

NMR (CDCl₃+CD₃OD, δ): 2.05-2.20 (2H, m), 2.70-3.10 (3H, m), 3.40-3.85(12H, m), 6.91-7.06 (4H, m), 7.25-7.37 (7H, m), 7.95-7.99 (2H, m).

MASS (m/z): 442 (free).

PREPARATION 172

To a suspension of4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic aciddihydrochloride salt (0.62 g) and 1-hydroxybenzotriazole (0.2 g) indichloromethane (12 ml) was added1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (0.22 g) and stirred for22 hours at ambient temperature. The reaction mixture was added to amixture of water and dichloromethane. The organic layer was taken anddried over magnesium sulfate. The magnesium sulfate was filtered off,and the filtrate was evaporated under reduced pressure to give4-[4-[4-(4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acidbenzotriazol-1-yl ester (0.41 g).

IR (KBr): 1780.0, 1600.6, 1513.8, 1230.4 cm⁻¹.

NMR (CDCl₃, δ): 1.85-2.05 (4H, m), 2.60-2.90 (3H, m), 3.25-3.80 (10H,m), 6.95-7.55 (15H, m), 8.08-8.18 (2H, m).

MASS (m/z): 559 (M⁺+1).

PREPARATION 173

To a suspension of 4-hydroxy-4-phenylpiperidine (5 g) and triethylamine(4.32 ml) in dichloromethane (50 ml) was added dropwisedi-tert-butyldicarbonate (6.16 g) in dichloromethane (6 ml) underice-cooling. The reaction mixture was then stirred for 4 hours atambient temperature. The reaction mixture was pulverized with water. Theorganic layer was separated, washed with brine, dried over magnesiumsulfate. The magnesium sulfate was filtered off, and the filtrate wasevaporated under reduced pressure. The residue was purified by columnchromatography over silica using dichloromethane/methyl alcohol (30:1)as the elution to give 4-hydroxy-4-phenylpiperidine-1-carboxylic acidtert-butyl ester (7.2 g).

IR (KBr): 3463.5, 1675.8, 1664.3, 1170.6 cm⁻¹.

NMR (CDCl₃, δ): 1.48 (9H, s), 1.63-2.08 (5H, m), 3.19-3.30 (2H, m),3.90-4.10 (2H, m), 7.27-7.50 (5H, m).

MASS (m/z): 178 (M⁺−Boc+1).

PREPARATION 174

To a solution of 4-hydroxy-4-phenylpiperidine-1-carboxylic acidtert-butyl ester (7.1 g) in N,N-dimethylformamide (71 ml) was added 60%sodium hydride in mineral oil (1.13 g) under ice-cooling, and stirredfor 1 hour at ambient temperature. The suspension was then stirred for1.5 hours at 60° C. To the reaction mixture was added iodomethane (32ml) at 40° C., and stirred for 30 minutes at 45° C. Water and ethylacetate were added with stirring, and the organic layer was separated,washed with brine, dried over magnesium sulfate. The magnesium sulfatewas filtered off, and the filtrate was evaporated under reducedpressure. The residue was purified by column chromatography over silicausing n-hexane/ethyl acetate (4:1) as the elution to give4-methoxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (6.63g).

IR (KBr): 1700.9, 1685.5, 1170.6 cm⁻¹.

NMR (CDCl₃, δ): 1.47 (9H, s), 1.79-2.05 (4H, m), 2.98 (3H, s), 3.12-3.24(2H, m), 3.90-4.10 (2H, m), 7.28-7.39 (5H, m).

MASS (m/z): 192 (M⁺−Boc+1).

PREPARATION 175

To a solution of 4-methoxy-4-phenylpiperidine-1-carboxylic acidtert-butyl ester (6.5 g) in ethyl acetate (65 ml) was added dropwise4N-HCl/ethyl acetate (56 ml) at ambient temperature. The reactionmixture was stirred for 1.5 hours at ambient temperature. To thereaction mixture was added diisopropyl ether. The precipitate wascollected by filtration to give powder. The powder was adjusted to pH 11with 1N-NaOH, and extracted with ethyl acetate. The organic layer wasseparated, washed with brine, dried over magnesium sulfate. Themagnesium sulfate was filtered off, and the filtrate was evaporatedunder reduced pressure to give 4-methoxy-4-phenylpiperidine (3.47 g).

IR (KBr): 3322.7, 1535.1, 1070.3 cm⁻¹.

NMR (CDCl₃, δ): 1.80-2.07 (5H, m), 2.88-3.15 (7H, m), 7.28-7.44 (5H, m).

MASS (m/z): 192 (M⁺+1).

PREPARATION 176

A mixture of 1-acetyl-4-(4-trifluoromethanesulfonyloxyphenyl)piperazine(3 g), 4-methoxy-4-phenylpiperidine (1.63 g), acetic acid palladium(II)salt (0.11 g), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.42g) and cesium carbonate (3.88 g) in toluene (17 ml) was stirred for 30minutes at ambient temperature. After being stirred for a further 17hours at 100° C., the reaction mixture was diluted with dichloromethane.The suspension was filtered through celite, and the filtrate wasevaporated under reduced pressure. The residue was purified by columnchromatography over silica using ethyl acetate/methyl alcohol (30:1) asthe elution to give1-acetyl-4-[4-(4-methoxy-4-phenylpiperidin-1-yl)phenyl]piperazine (2.65g).

IR (KBr): 1643.1, 1321.0, 1074.2 cm⁻¹.

NMR (CDCl₃, δ): 2.14 (3H, s), 2.14-2.17 (4H, m), 2.98 (3H, s), 2.98-3.45(8H, m), 3.59-3.79 (4H, m), 6.92-7.00 (4H, m), 7.28-7.47 (5H, m).

MASS (m/z): 394 (M⁺+1).

PREPARATION 177

A mixture of1-acetyl-4-[4-(4-methoxy-4-phenylpiperidin-1-yl)phenyl]piperazine (2.5g) and 10% NaOH aq. (10.2 ml) in ethyl alcohol (50 ml) was refluxed for23.5 hours. The reaction mixture was evaporated under reduced pressure.The residue was washed with water, and dried to give1-[4-(4-methoxy-4-phenylpiperidin-1-yl)phenyl]piperazine (2.18 g).

IR (KBr): 3290.0, 1513.8, 1232.3, 1074.2 cm⁻¹.

NMR (DMSO-d₆, δ): 1.91-2.11 (4H, m), 2.80-3.17 (11H, m), 3.20-3.45 (5H,m), 6.79-6.91 (4H, m), 7.25-7.46 (5H, m).

MASS (m/z): 352 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 170.

PREPARATION 1784-[4-[4-(4-Methoxy-4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoicacid ethyl ester

IR (KBr): 1702.8, 1511.9, 1236.1, 1105.0 cm⁻¹.

NMR (CDCl₃, δ): 1.37 (3H, t, J=7.1 Hz), 2.14-2.18 (4H, m), 3.01 (3H, s),3.06-3.50 (12H, m), 4.34 (2H, q, J=7.1 Hz), 6.90-7.03 (6H, m), 7.28-7.47(5H, m), 7.93-7.98 (2H, m).

MASS (m/z): 500 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 170.

PREPARATION 1794-[4-[4-(4-Methoxy-4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl]benzoicacid dihydrochloride

IR (KBr): 2960.2, 1702.8, 1604.5, 1184.1 cm⁻¹.

NMR (DMSO-d₆, δ): 2.20-3.70 (19H, m), 7.02-7.62 (11H, m), 7.78-7.83 (2H,m).

MASS (m/z): 472 (M⁺+1) (free).

The following compound was obtained according to a similar manner tothat of Preparation 172.

PREPARATION 1804-(4-[4-(4-Methoxy-4-phenylpiperidin-1-yl)phenyl]piperazin-1-yl)benzoicacid benzotriazol-1-yl ester

IR (KBr): 1762.6, 1600.6, 1230.4, 1184.1 cm⁻¹.

NMR (CDCl₃, δ): 2.10-2.20 (4H, m), 3.01 (3H, s), 3.05-3.64 (12H, m),6.98-7.04 (6H, m), 7.32-7.51 (8H, m), 8.07-8.17 (3H, m).

MASS (m/z): 589 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 176.

PREPARATION 1811-[4-[4-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]piperazin-1-yl]ethanone

IR (KBr): 1648.8, 1637.3, 1334.5, 1230.4, 1099.2 cm⁻¹.

NMR (DMSO-d₆, δ): 1.67-1.73 (4H, m), 2.03 (3H, s), 2.90-3.14 (8H, m),3.50-3.60 (4H, m), 3.90 (4H, s), 6.86 (4H, s).

MASS (m/z): 346 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 177.

PREPARATION 182 8-(4-Piperazinylphenyl)-1,4-dioxa-8-azaspiro[4.5]decane

IR (KBr): 3284.2, 1513.8, 1328.7, 1110.8 cm⁻¹.

NMR (DMSO-d₆, δ): 1.70 (4H, t, J=5.7 Hz), 2.79-2.91 (8H, m), 3.06-3.12(4H, m), 3.25-3.38 (5H, m), 6.77-6.88 (4H, m).

MASS (m/z): 304 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 170.

PREPARATION 1834-[4-[4-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]piperazin-1-yl]benzoicacid ethyl ester

IR (KBr): 1704.8, 1511.9, 1224.6, 1108.9 cm⁻¹.

NMR (CDCl₃, δ): 1.37 (3H, t, J=7.1 Hz), 1.86 (4H, t, J=5.7 Hz),3.20-3.25 (8H, m), 3.45-3.50 (4H, m), 3.99 (4H, s), 4.34 (2H, q, J=7.1Hz), 6.89-6.93 (6H, m), 7.91-7.97 (2H, m).

MASS (m/z): 452 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 171.

PREPARATION 1844-[4-[4-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]piperazin-1-yl]benzoicacid dihydrochloride

IR (KBr): 2962.1, 1670.1, 1321.0, 1230.4 cm⁻¹.

NMR (DMSO-d₆, δ): 1.70-2.00 (4H, m), 3.10-3.70 (16H, m), 7.00-7.20 (6H,m), 7.78-7.82 (2H, m).

MASS (m/z): 424 (M⁺+1) (free).

The following compound was obtained according to a similar manner tothat of Preparation 172.

PREPARATION 1854-[4-[4-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]piperazin-1-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1781.9, 1600.6, 1232.3 cm⁻¹.

NMR (CDCl₃, δ): 1.86 (4H, t, J=5.7 Hz), 3.21-3.28 (8H, m), 3.59-3.64(4H, m), 4.00 (4H, s), 6.95-7.02 (6H, m), 7.40-7.58 (3H, m), 8.07-8.17(3H, s).

MASS (m/z): 541 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 176.

PREPARATION 1861-Acetyl-4-[4-(4-cyclohexyloxypiperidin-1-yl)phenyl]piperazine

IR (KBr): 1621.8, 1236.1, 1101.2 cm⁻¹.

NMR (CDCl₃, δ): 1.20-2.00 (14H, m), 2.13 (3H, s), 2.75-3.78 (14H, m),6.78-7.83 (4H, m).

MASS (m/z): 386 (M⁺+1).

PREPARATION 187

A mixture of1-acetyl-4-[4-(4-cyclohexyloxypiperidin-1-yl)phenyl]piperazine (0.37 g)and 10% sodium hydroxide (1.9 ml) in ethyl alcohol (7.4 ml) was refluxedfor 10 hours. The reaction mixture was evaporated under reducedpressure. The residue was washed with water, and dried to give1-[4-(4-cyclohexyloxypiperidin-1-yl)phenyl]piperazine (0.32 g).

The following compound was obtained according to a similar manner tothat of Preparation 170.

PREPARATION 1884-[4-[4-(4-Cyclohexyloxypiperidin-1-yl)phenyl]piperazin-1-yl]benzoicacid ethyl ester

IR (KBr): 1706.7, 1234.2, 1110.8 cm⁻¹.

NMR (CDCl₃, δ): 1.23-1.91 (17H, m), 2.77-2.86 (2H, m), 3.19-3.24 (4H,m), 3.30-3.60 (8H, m), 4.34 (2H, q, J=7.1 Hz), 6.89-6.93 (6H, m),7.93-7.97 (2H, m).

MASS (m/z): 492 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 171.

PREPARATION 1894-[4-[4-(4-Cyclohexyloxypiperidin-1-yl)phenyl]piperazin-1-yl]benzoicacid dihydrochloride

IR (KBr): 1672.0, 1322.9, 1230.4 cm⁻¹.

NMR (DMSO-d₆, δ): 1.00-2.20 (14H, m), 3.20-4.00 (14H, m), 6.80-8.00 (8H,m).

MASS (m/z): 464 (M⁺+1) (free).

The following compound was obtained according to a similar manner tothat of Preparation 172.

PREPARATION 1904-[4-[4-Cyclohexyloxypiperidin-1-yl)phenyl]piperazin-1-yl]benzoic acidbenzotriazol-1-yl ester

IR (KBr): 1781.9, 1600.6, 1513.8, 1230.4 cm⁻¹.

NMR (CDCl₃, δ): 1.13-2.10 (14H, m), 2.80-2.88 (2H, m), 3.22-3.64 (12H,m), 6.94-7.02 (6H, m), 7.39-7.58 (3H, m), 8.07-8.17 (3H, m).

MASS (m/z): 581 (M⁺+1).

PREPARATION 191

To a suspension of 1-(4-hydroxyphenyl)piperazine (50 g) and potassiumcarbonate (46.5 g) in N,N-dimethylformamide (100 ml) was added dropwisebenzyl chloroformate (47.86 g) at 0 to 10° C., and stirred for 4 hoursat ambient temperature. The reaction mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with brineand dried, and the solvent was evaporated under reduced pressure. Theresidue was chromatographed on a column of silica gel eluting withdichloromethane/methyl alcohol (30:1) to give4-(4-hydroxyphenyl)piperazine-1-carboxylic acid benzyl ester (60.8 g).

IR (KBr): 3336.2, 1658.5, 1226.5 cm⁻¹.

NMR (CDCl₃, δ): 3.00 (4H, t, J=4.9 Hz), 3.66 (4H, t, J=5.1 Hz), 5.16(2H, s), 5.29 (1H, s), 6.74-6.86 (4H, m), 7.30-7.40 (5H, m).

MASS (m/z): 313 (M⁺+1).

PREPARATION 192

To a solution of 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid benzylester (22.38 g) and pyridine (8.7 ml) in dichloromethane (336 ml) wasadded dropwise trifluoromethanesulfonic anhydride (15.7 ml) at 0 to 10°C., and stirred for 2 hours. The reaction mixture was washedsuccessively with 0.5N hydrochloric acid, saturated sodium hydrogencarbonate, water, brine, dried, and evaporated under reduced pressure.The residue was chromatographed on a column of silica gel eluting withdichloromethane/methyl alcohol (50:1) to give4-(4-trifluoromethanesulfonyloxyphenyl)piperazine-1-carboxylic acidbenzyl ester (21.06 g).

IR (KBr): 1685.5, 1511.9, 1427.1 cm⁻¹.

NMR (CDCl₃, δ): 3.17 (4H, t, J=5.0 Hz), 3.67 (4H, t, J=5.2 Hz), 5.16(2H, s), 6.87-7.18 (4H, m), 7.34-7.38 (5H, m).

MASS (m/z): 445 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 176.

PREPARATION 1934-[4-(1,4-Dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]piperazine-1-carboxylicacid benzyl ester

IR (KBr): 1697.1, 1519.6, 1230.4 cm⁻¹.

NMR (CDCl₃, δ): 1.85 (4H, t, J=5.7 Hz), 3.00-3.05 (4H, m), 3.21 (4H, t,J=5.7 Hz), 3.65 (4H, t, J=5.1 Hz), 3.99 (4H, s), 5.16 (2H, s), 6.84-6.95(4H, m), 7.36-7.39 (5H, m).

MASS (m/z): 438 (M⁺+1).

PREPARATION 194

To a solution of4-[4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]piperazine-1-carboxylicacid benzyl ester (30 g) in 1,4-dioxane (450 ml) was added1N-hydrochloric acid (240 ml) at ambient temperature, and the mixturewas stirred for 7 hours at 90° C. The reaction mixture was poured intowater. The mixture was adjusted to pH 10-12 with 1N-sodium hydroxide(480 ml), and extracted with ethyl acetate. The organic layer was washedwith water, brine, and dried, and evaporated under reduced pressure. Theresidue was chromatographed on a column of silica gel eluting withdichloromethane/methyl alcohol (50:1) to give4-[4-(4-oxopiperidin-1-yl)phenyl]piperazine-1-carboxylic acid benzylester (21.22 g).

IR (KBr): 1718.3, 1683.6, 1232.3 cm⁻¹.

NMR (CDCl₃, δ): 2.55 (4H, t, J=6.0 Hz), 3.05 (4H, t, J=4.8 Hz), 3.49(4H, t, J=6.0 Hz), 3.66 (4H, t, J=5.1 Hz).

MASS (m/z): 394 (M⁺+1).

PREPARATION 195

To a suspension of 4-(4-chlorophenyl)-4-hydroxypiperidine (8 g) andtriethylamine (5.8 ml) in dichloromethane (80 ml) was addeddi-tert-butyldicarbonate (9.07 g) under ice-cooling. The suspension wasthen stirred for 5 hours at ambient temperature. The reaction mixturewas evaporated under reduced pressure. The residue was diluted withethyl acetate and washed with water, washed with brine, and dried overmagnesium sulfate. The magnesium sulfate was filtered off, and thefiltrate was evaporated under reduced pressure. The residue was purifiedby column chromatography over silica using n-hexane/ethyl acetate (3:1)as the elution to give4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butylester (11.76 g).

IR (KBr): 3461.6, 1675.8, 1662.3, 1166.7 cm⁻¹.

NMR (CDCl₃, δ): 1.48 (9H, s), 1.62-2.04 (5H, m), 3.16-3.28 (2H, m),3.97-4.09 (2H, m), 7.30-7.44 (4H, m).

MASS (m/z): 212 (M⁺−Boc).

The following compound was obtained according to a similar manner tothat of Preparation 174.

PREPARATION 196 4-(4-Chlorophenyl-4-methoxypiperidine-1-carboxylic acidtert-butyl ester

IR (KBr): 1695.1, 1423.2, 1170.6 cm⁻¹.

NMR (CDCl₃, δ): 1.47 (9H, s), 1.72-2.04 (4H, m), 2.97 (3H, s), 3.07-3.22(2H, m), 3.90-4.04 (2H, m), 7.27-7.37 (4H, m).

MASS (m/z): 348.1 (M⁺+Na).

The following compound was obtained according to a similar manner tothat of Preparation 175.

PREPARATION 197 4-(4-Chlorophenyl)-4-methoxypiperidine

IR (Film): 3305.4, 1490.7, 1135.9, 1072.2 cm⁻¹.

NMR (CDCl₃, δ): 1.75-2.03 (4H, m), 2.86-3.11 (8H, m), 7.33 (4H, s).

MASS (m/z): 226.2.

The following compound was obtained according to a similar manner tothat of Preparation 164.

PREPARATION 198 1-(4-Nitrophenyl)-4-(4-chlorophenyl)-4-methoxypiperidine

IR (KBr): 1594.8, 1319.1, 1066.4 cm⁻¹.

NMR (CDCl₃, δ): 1.91-2.20 (4H, m), 3.02 (3H, s), 3.34-3.48 (2H, m),3.79-3.86 (2H, m), 6.83-6.91 (2H, m), 7.29-7.39 (4H, m), 8.09-8.17 (2H,m).

MASS (m/z): 347.2.

PREPARATION 199

A mixture of 1-(4-nitrophenyl)-4-(4-chlorophenyl)-4-methoxypiperidine(8.9 g), iron powder (10.7 g) and ammonium chloride (1.07 g) in ethanol(445 ml) and water (44.5 ml) was stirred at reflux for 5.5 hours. Theinsoluble material was filtered off, and the filtrate was evaporatedunder reduced pressure. To the residue was added a mixture of ethylacetate (150 ml), water (100 ml) and saturated sodium hydrogen carbonate(50 ml). The organic layer was separated, washed with brine, dried overmagnesium sulfate. The magnesium sulfate was filtered off, and thefiltrate was evaporated under reduced pressure. To the residue was addeda mixture of diisopropyl ether (10 ml) and n-hexane (20 ml). Theprecipitate was collected by filtration, and dried under reducedpressure to give1-(4-aminophenyl)-4-(4-chlorophenyl)-4-methoxypiperidine (7.3 g).

IR (KBr): 3342.0, 1614.1, 1517.7, 1066.4 cm⁻¹.

NMR (CDCl₃, δ): 2.04-2.20 (4H, m), 2.99 (3H, s), 3.03-3.34 (6H, m),6.64-6.70 (4H, m), 7.30-7.45 (4H, m).

MASS (m/z): 317.3.

The following compound was obtained according to a similar manner tothat of Preparation 166.

PREPARATION 200 1-(4-Bromophenyl)-4-(4-chlorophenyl)-4-methoxypiperidine

IR (KBr): 1589.1, 1494.6, 1249.6, 1062.6 cm⁻¹.

NMR (CDCl₃, δ): 1.96-2.15 (4H, m), 2.99 (3H, s), 3.08-3.22 (2H, m),3.40-3.55 (2H, m), 6.81-6.87 (2H, m), 7.30-7.38 (6H, m).

MASS (m/z): 382 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 167.

PREPARATION 2014-[4-[4-(4-Chlorophenyl)-4-methoxypiperidin-1-yl]phenyl]piperazine-1-carboxylicacid tert-butyl ester

IR (KBr): 1695.1, 1511.9, 1234.2 cm⁻¹.

NMR (CDCl₃, δ): 1.48 (9H, s), 2.05-2.15 (4H, m), 2.99 (3H, s), 3.00-3.16(6H, m), 3.37-3.43 (2H, m), 3.55-3.60 (4H, m), 6.87-6.99 (4H, m), 7.35(4H, s).

MASS (m/z): 486 (M⁺+1).

PREPARATION 202

To a solution of4-[4-[4-(4-chlorophenyl)-4-methoxypiperidin-1-yl]phenyl]piperazine-1-carboxylicacid tert-butyl ester (1.56 g) in ethyl acetate (62 ml) was addeddropwise 4N-HCl/ethyl acetate (40 ml) at ambient temperature. Thereaction mixture was stirred for 33 hours at ambient temperature. Theprecipitate was collected by filtration, and dried under reducedpressure to give4-[4-[4-(4-chlorophenyl)-4-methoxypiperidin-1-yl]phenyl]piperazinetrihydrochloride salt (1.52 g).

IR (KBr): 3382.5, 1504.2, 1255.4 cm⁻¹.

NMR (DMSO₆, δ): 2.24-3.76 (20H, m), 7.12-7.84 (8H, m).

MASS (m/z): 386 (free).

The following compound was obtained according to a similar manner tothat of Preparation 169.

PREPARATION 2034-[4-[4-(4-Chlorophenyl)-4-methoxypiperidin-1-yl]phenyl]piperazine

The following compound was obtained according to a similar manner tothat of Preparation 170.

PREPARATION 2044-[4-[4-[4-(4-Chlorophenyl)-4-methoxypiperidin-1-yl]phenyl]piperazin-1-yl]benzoicacid ethyl ester

IR (KBr): 1702.8, 1602.6, 1513.8, 1234.2 cm⁻¹.

MASS (m/z): 534 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 171.

PREPARATION 2054-[4-[4-[4-(4-Chlorophenyl)-4-methoxypiperidin-1-yl]phenyl]piperazin-1-yl]benzoicacid dihydrochloride

IR (KBr): 2962.1, 1697.1, 1602.6, 1515.8, 1224.6 cm⁻¹.

MASS (m/z): 506 (M⁺+1) (free).

The following compound was obtained according to a similar manner tothat of Preparation 172.

PREPARATION 2064-[4-[4-[4-(4-Chlorophenyl)-4-methoxypiperidin-1-yl]phenyl]piperazin-1-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1772.3, 1762.6, 1598.7, 1230.4, 1184.1 cm⁻¹.

NMR (CDCl₃+CD₃OD, δ): 2.11-2.17 (3H, m), 3.01 (3H, s), 3.05-3.66 (12H,m), 6.95-7.04 (6H, m), 7.37-7.60 (7H, m), 8.07-8.17 (3H, m).

MASS (m/z): 623 (M⁺+1).

PREPARATION 207

60% Sodium hydride (1.01 g) was added slowly to a suspension of4,4′-bicyclohexanol (5 g) in N,N-dimethylformamide (50 ml) at ambienttemperature, and the mixture was stirred for 6 hours at 80° C. To themixture was added dropwise n-propylbromide (2.29 ml) at 0-5° C., and thereaction mixture was stirred for 18.5 hours at 80° C. The reactionmixture was poured into water, and extracted with ethyl acetate. Theorganic layer was washed with brine and dried, and the solvent wasevaporated under reduced pressure. The residue was chromatographed on acolumn of silica gel eluting with dichloromethane/methyl alcohol (50:1)to give 4′-propyl-4-hydroxy-1,1′-bicyclohexane (1.21 g).

IR (KBr): 3363.2, 1454.1, 1101.2 cm⁻¹.

NMR (CDCl₃, δ): 0.67-2.08 (24H, m), 2.88-3.60 (4H, m).

PREPARATION 208

To a solution of 4′-propoxybicyclohexyl-4-ol (1 g) and triethylamine(0.81 ml) in dichloromethane (10 ml) was added dropwise methanesulfonylchloride (0.39 ml) at 0-5° C., and stirred for 3 hours. The reactionmixture was washed with water and brine, and dried, and evaporated underreduced pressure to give4′-propoxy-4-methylsulfonyloxy-1,1′-bicyclohexane (1.44 g).

IR (KBr): 1454.1, 1351.9, 1338.4, 1164.8, 1110.8 cm⁻¹.

NMR (CDCl₃, δ): 0.87-2.20 (23H, m), 2.89-3.44 (7H, m).

PREPARATION 209

A mixture of 4-piperazinylbenzoic acid ethyl ester (1.03 g),4′-propoxy-4-methylsulfonyloxy-1,1′-bicyclohexane (1.4 g), potassiumcarbonate (0.91 g) in N,N-dimethylformamide (10 ml) was stirred for 8hours at 130° C. The reaction mixture was poured into water, andextracted with ethyl acetate. The organic layer was washed with brineand dried, and the solvent was evaporated under reduced pressure. Theresidue was chromatographed on a column of silica gel eluting withdichloromethane/methyl alcohol (200:1) to give4-[4-(4′-propoxy-1,1′-bicyclohexan-4-yl)piperazin-1-yl]benzoic acidethyl ester (0.26 g).

IR (KBr): 1706.7, 1286.3, 1108.9 cm⁻¹.

NMR (CDCl₃, δ): 0.88-2.20 (26H, m), 3.00-3.67 (1H, m), 4.33 (2H, q,J=7.1 Hz), 6.85-6.89 (2H, m), 7.92-7.97 (2H, m).

MASS (m/z): 455.

The following compound was obtained according to a similar manner tothat of Preparation 171.

PREPARATION 2104-[4-(4′-Propoxy-1,1′-bicyclohexan-4-yl)piperazin-1-yl]benzoic acidhydrochloride

IR (KBr): 1695.1, 1228.4, 1112.7 cm⁻¹.

NMR (CDCl₃, δ): 0.88-2.03 (23H, m), 3.10-3.66 (12H, m), 6.86-6.91 (2H,m), 7.98-8.02 (2H, m).

MASS (m/z): 455.

The following compound was obtained according to a similar manner tothat of Preparation 172.

PREPARATION 2114-[4-(4′-Propoxy-1,1′-bicyclohexan-4-yl)piperazin-1-yl]benzoic acidbenzotriazol-1-yl ester

IR (KBr): 1772.3, 1695.1, 1226.5, 1187.9, 1089.6 cm⁻¹.

NMR (CDCl₃, δ): 0.88-2.04 (23H, m), 3.10-3.69 (12H, m), 6.93-6.98 (2H,m), 7.39-8.17 (6H, m).

PREPARATION 212

Lithium aluminum hydride (7.94 g) was added slowly to stirredtetrahydrofuran (80 ml) at ambient temperature. To the mixture was addeddropwise 3,3-tetramethyleneglutamide (7 g) in tetrahydrofuran (70 ml) atambient temperature. After refluxed for 5 hours, to the reaction mixturewas added dropwise water, and the mixture was filtered. The filtrate wasevaporated under reduced pressure to give an oil (4.7 g). To the residuewas added tetrahydrofuran (47 ml) and triethylamine (6.12 ml). To themixture was added dropwise benzyloxycarbonyl chloride (5.76 g) intetrahydrofuran (6 ml) at ambient temperature. After stirring for 1.5hours, the reaction mixture was poured into water, and extracted withethyl acetate. The organic layer was separated, washed with dilutedhydrochloric acid, water, brine, and dried, and evaporated under reducedpressure to give an oil (8.52 g). The oil was chromatographed on asilica gel eluting with a mixture of dichloromethane and methyl alcohol(100:1) to give an oil (5.51 g). A solution of this oil (5.51 g) inmethyl alcohol (55 ml) was added 10% palladium on carbon (0.55 g), andhydrogen gas at atmospheric pressure for 6 hours. The reaction mixturewas filtered through celite and evaporated under reduced pressure togive 8-azaspiro[4.5]decane (2.49 g).

IR (KBr): 3249.5, 1531.2, 1467.6 cm⁻¹.

NMR (CDCl₃, δ): 1.40-1.64 (13H, m), 2.84 (4H, br s).

MASS (m/z): 140 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 176.

PREPARATION 2131-[4-[4-(8-Azaspiro[4.5]decan-8-yl)phenyl]piperazin-1-yl]ethanone

IR (KBr): 2937.1, 1648.8, 1515.8, 1238.1 cm⁻¹.

NMR (CDCl₃, δ): 1.42-1.67 (12H, m), 2.13 (3H, s), 3.03-3.08 (8H, m),3.58-3.63 (2H, m), 3.73-3.79 (2H, m), 6.78-7.86 (4H, m).

MASS (m/z): 342 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 177.

PREPARATION 214 6-(Piperazinylphenyl)-8-azaspiro[4.5]decane

The following compound was obtained according to a similar manner tothat of Preparation 170.

PREPARATION 2154-[4-[4-(8-Azaspiro[4.5]decan-8-yl)phenyl]piperazin-1-yl]benzoic acidethyl ester

IR (KBr): 1706.7, 1322.9, 1282.4, 1236.1, 1105.0 cm⁻¹.

NMR (CDCl₃, δ): 1.37 (3H, t, J=7.1 Hz), 1.41-1.65 (12H, m), 3.03-3.09(4H, m), 3.19-3.24 (4H, m), 3.45-3.50 (4H, m), 4.34 (2H, q, J=7.1 Hz),6.89-6.94 (6H, m), 7.93-7.97 (2H, m).

MASS (m/z): 448 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 171.

PREPARATION 2164-[4-[4-(8-Azaspiro[4.5]decan-8-yl)phenyl]piperazin-1-yl]benzoic aciddihydrochloride

IR (KBr): 2946.7, 1689.3, 1388.5, 1226.5, 1184.1 cm⁻¹.

NMR (DMSO-d₆, δ): 1.40-2.40 (12H, m), 3.00-4.20 (12H, m), 7.01-7.15 (4H,m), 7.69-7.74 (2H, m), 7.78-7.83 (2H, m), 12.06 (1H, br s).

MASS (m/z): 420 (M⁺+1) (free).

The following compound was obtained according to a similar manner tothat of Preparation 172.

PREPARATION 2174-[4-[4-(8-Azaspiro[4.5]decan-8-yl)phenyl]piperazin-1-yl]benzoic acidbenzotriazol-1-yl ester

IR (KBr): 1781.9, 1598.7, 1513.8, 1228.4 cm⁻¹.

NMR (CDCl₃, δ): 1.43-1.73 (2H, m), 3.05-3.10 (4H, m), 3.22-3.27 (4H, m),3.59-3.64 (4H, m), 6.90-7.02 (6H, m), 7.39-7.58 (3H, m), 8.07-8.17 (3H,m).

MASS (m/z): 537 (M⁺+1).

PREPARATION 218

To a solution of 4-acetyl-1-(4-hydroxyphenyl)piperazine (20 g) andpyridine (11.02 ml) in dichloromethane (60 ml) was added dropwise withstirring trifluoromethanesulfonic acid anhydride (20 ml) at 0° C. Themixture was then stirred for 1 hour at 0° C. and 1 hour at roomtemperature. The reaction mixture was added to a mixture of 0.5 mol/lhydrochloric acid and dichloromethane. The organic layer was washed withsodium hydrogen carbonate solution and sodium chloride solution. Theorganic layer was taken and dried over magnesium sulfate. The magnesiumsulfate was filtered off, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel chromatography(30:1 dichloromethane-methanol elution). Diisopropyl ether was added tothe residue, and precipitates were filtered, washed with the samesolvent, and dried to give trifluoromethanesulfonic acid4-(4-acetylpiperazin-1-yl)phenyl ester (27.78 g).

NMR (CDCl₃, δ): 2.15 (3H, s), 3.20 (4H, m), 3.63 (2H, t, J=5.2 Hz), 3.78(2H, t, J=5.2 Hz), 6.88-6.95 (2H, m), 7.15-7.20 (2H, m).

MASS (m/z): 353 (M⁺+1).

PREPARATION 219

To a mixture of cesium carbonate (25.32 g), palladium(II) acetate (0.624g) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (2.59 g) in toluene(110 ml) was successively added cis-2,6-dimethylmorpholine (8.21 ml) andtrifluoromethanesulfonic acid 4-(4-acetylpiperazin-1-yl)phenyl ester (20g) in stream of nitrogen. The mixture was stirred at ambient temperaturefor 30 minutes and at 100° C. for further 12 hours. After cooling toroom temperature, water was added to the reaction mixture. The resultingprecipitates were filtered, washed with water and dried. The residue waspurified by silica gel chromatography (50:1 dichloromethane-methanolelution) to give1-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]ethanone(7.78 g).

NMR (CDCl₃, δ): 1.15-1.30 (6H, m), 2.13 (3H, s), 2.36 (2H, t, J=11.1Hz), 3.00-3.90 (12H, m), 6.85-7.00 (4H, m).

MASS (m/z): 318 (M⁺+1).

PREPARATION 220

A mixture1-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]ethanone(11.37 g) and 1.0 mol/l hydrochloric acid (225 ml) in ethanol (220 ml)was refluxed for 23 hours. The reaction mixture was added to a mixtureof 1.0 mol/l sodium hydroxide solution and dichloromethane. The organiclayer was taken and dried over magnesium sulfate. The magnesium sulfatewas filtered off, and the filtrate was concentrated under reducedpressure to give cis-2,6-dimethyl-4-(4-piperazinylphenyl)morpholine(3.64 g).

NMR (CDCl₃, δ): 1.24 (6H, d, J=6.3 Hz), 2.35 (2H, t, J=11.1 Hz),2.95-3.40 (11H, m), 3.70-3.9 (2H, m), 6.8-6.95 (4H, m).

MASS (m/z): 276 (M⁺+1).

PREPARATION 221

A solution of cis-2,6-dimethyl-4-(4-piperazinylphenyl)morpholine (2.00g), 4-fluorobenzoic acid ethyl ester (1.43 g) and potassium carbonate(1.01 g) in dimethylsulfoxide (40 ml) was stirred for 8 hours at 150°C., during which period additional 4-fluorobenzoic acid ethyl ester(1.35 g) and potassium carbonate (1.0 g) was added to the mixture. Thereaction mixture was added to a mixture of water and dichloromethane.The organic layer was taken and dried over magnesium sulfate. Themagnesium sulfate was filtered off, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (25:1 dichloromethane-methanol elution) to give4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoicacid ethyl ester (2.5 g).

IR (KBr): 1705, 1697 1605, 1513, 1282, 1234 cm⁻¹.

NMR (DMSO-d₆, δ): 1.25 (6H, d, J=6.3 Hz), 1.36 (3H, t, J=7.1 Hz), 2.37(2H, t, J=11.1 Hz), 3.15-3.55 (10H, m), 3.7-3.9 (2H, m), 4.34 (2H, q,J=7.1 Hz), 6.85-7.00 (6H, m), 7.95 (2H, d, J=8.9 Hz).

MASS (m/z): 424 (M⁺+1).

PREPARATION 222

A mixture of4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoicacid ethyl ester (2.46 g) and 1.0 mol/l sodium hydroxide solution (11.6ml) in a mixed solvent of ethanol (50 ml) and tetrahydrofuran (125 ml)was refluxed for 33 hours, during which period additional 1.0 mol/lsodium hydroxide solution (24 ml) was added to the mixture. Aftercooling to ambient temperature, the reaction mixture was poured intocold water, and the mixture was adjusted to pH 2 with 1.0 mol/lhydrochloric acid. The resulting precipitates were filtered, washed withwater and dried to give4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoicacid (1.05 g).

IR (KBr): 1664, 1603, 1514, 1234 cm⁻¹.

NMR (DMSO-d₆, δ): 1.14 (6H, d, J=6.21 Hz), 2.16 (2H, t, J=11.0 Hz),3.05-3.80 (12H, m), 6.80-7.15 (6H, m), 7.79 (2H, d, J=8.8 Hz).

MASS (m/z): 472 (M⁺+1).

PREPARATION 223

A mixture of4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoicacid (1.01 g), 1-hydroxybenzotriazole (370 mg) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (986 mg) inmethylene chloride (100 ml) was stirred for 4 hours at room temperaturethen evaporated under reduced pressure. Water was added to the residueand the resulting precipitate collected by filtration, washed withwater, then dried under hi-vacuum to give4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoicacid benzotriazol-1-yl ester (1.197 g).

IR (KBr): 1784, 1603, 1512, 1232 cm⁻¹.

NMR (CDCl₃, δ): 1.26 (6H, d, J=6.3 Hz), 2.38 (2H, t, J=11.0 Hz),3.15-3.45 (6H, m), 3.62 (4H, t, J=5.1 Hz), 3.7-3.95 (2H, m), 6.8-7.1(6H, m), 7.3-7.6 (3H, m), 8.0-8.25 (3H, m).

MASS (m/z): 589 (M⁺+1).

PREPARATION 224

To a mixture of cesium carbonate (6.33 q), palladium(II) acetate (156mg) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (648 mg) in dioxane(28 ml) was successively addedcis-2,6-dimethyl-4-(4-piperazinylphenyl)morpholine (4.59 g) and4′-trifluoromethanesulfonyloxy-1,1′-biphenyl-4-carboxylic acid methylester (5 g) in a stream of nitrogen. The mixture was stirred at ambienttemperature for 30 minutes and at 80° C. for a further 28 hours. Aftercooling to room temperature, water was added to the reaction mixture.The resulting precipitates were filtered, washed with water and dried togive4′-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]-1,1′-biphenyl-4-carboxylicacid methyl ester (3.72 g).

NMR (CDCl₃, δ): 1.26 (6H, d, J=6.3 Hz), 2.37 (2H, t, J=11.0 Hz), 3.2-3.5(10H, m), 3.75-3.9 (2H, m), 3.93 (3H, s), 6.8-7.15 (6H, m), 7.5-7.7 (4H,m), 8.07 (2H, d, J=8.3 Hz).

MASS (m/z): 486 (M⁺+1).

PREPARATION 225

A mixture of4′-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]-1,1′-biphenyl-4-carboxylicacid methyl ester (3.70 g) and 1.0 mol/l sodium hydroxide solution (30ml) in a mixed solvent of methanol (75 ml) and tetrahydrofuran (185 ml)was refluxed for 15.5 hours. After cooling to ambient temperature, thereaction mixture was poured into cold water, and the mixture wasadjusted to pH 2 with 1.0 mol/l hydrochloric acid. The resultingprecipitates were filtered, washed with water and diisopropyl ether anddried to give4′-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]-1,1′-biphenyl-4-carboxylicacid (3.68 g).

MASS (m/z): 472 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 2264′-[4-[4-(2,6-Dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]-1,1′-biphenyl-4-carboxylicacid benzotriazol-1-yl ester

NMR (DMSO-d₆, δ): 1.26 (6H, d, J=6.3 Hz), 2.38 (2H, t, J=11.0 Hz),3.2-3.6 (10H, m), 3.7-3.95 (2H, m), 6.85-7.15 (6H, m), 7.4-7.9 (7H, m),8.12 (2H, d, J=8.1 Hz), 8.31 (2H, d, J=8.5 Hz).

MASS (m/z): 589 (M⁺+1).

PREPARATION 227

A solution of 4-fluorobenzoic acid ethyl ester (3 g),cis-2,6-dimethylmorpholine (2.26 g) and potassium carbonate (2.47 g) indimethylsulfoxide (60 ml) was stirred for 18 hours at 80° C. Thereaction mixture was added to a mixture of water and ethyl acetate. Theorganic layer was taken and dried over magnesium sulfate. The magnesiumsulfate was filtered off, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel chromatography(5:1 hexane-ethyl acetate elution) to give4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid ethyl ester (555 mg).

IR (KBr): 1695, 1605, 1518, 1244 cm⁻¹.

NMR (CDCl₃, δ): 1.27 (6H, d, J=6.3 Hz), 1.37 (3H, t, J=7.1 Hz), 2.51(2H, t, J=11.4 Hz), 3.5-3.9 (4H, m), 4.33 (2H, q, J=7.1 Hz), 6.85 (2H,d, J=9 Hz), 7.93 (2H, d, J=8.9 Hz).

MASS (m/z): 250 (M⁺+1).

PREPARATION 228

To a solution of 4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid ethylester (0.55 g) in a mixed solvent of methanol (3 ml) and tetrahydrofuran(6 ml) was added hydrazine monohydrate (1.6 ml). The solution wasrefluxed for 20 hours, during which period additional hydrazinemonohydrate (1.6 ml) was added to the mixture. After cooling to ambienttemperature, the reaction mixture was added to a mixture of water andethyl acetate. The organic layer was washed with sodium chloridesolution. The organic layer was taken and dried over magnesium sulfate.The magnesium sulfate was filtered off, and the filtrate wasconcentrated under reduced pressure to give4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid hydrazide (489.7 mg).

IR (KBr): 1632, 1606, 1506, 1331, 1246 cm⁻¹.

NMR (DMSO-d₆, δ): 1.15 (6H, d, J=6.1 Hz), 2.3 (2H, t, J=11.4 Hz),3.55-3.8 (4H, m), 4.36 (2H, br s), 6.94 (2H, d, J=8.9 Hz), 7.71 (2H, d,J=8.8 Hz).

MASS (m/z): 250 (M⁺+1).

PREPARATION 229

A mixture of 4-(cis-2,6-dimethylmorpholin-4-yl)benzoic acid hydrazide(458 mg), 4-methoxycarbonylbenzoyl chloride (622 mg) and pyridine (5 ml)in tetrahydrofuran (10 ml) was stirred for 6 hours at 0° C. The reactionmixture was added to water. The resulting precipitates were filtered,washed with water and dried to give4-[N′-[4-(cis-2,6-dimethylmorpholin-4-yl)benzoyl]hydrazinocarbonyl]benzoicacid methyl ester (662.8 mg).

IR (KBr): 1724, 1606, 1279, 1242 cm⁻¹.

NMR (DMSO-d₆, δ): 1.17 (6H, d, J=6.1 Hz), 2.35 (2H, t, J=11.2 Hz),3.6-3.85 (4H, m), 3.9 (3H, s), 7.02 (2H, d, J=8.9 Hz), 7.83 (2H, d,J=8.8 Hz), 8.0-8.2 (4H, m), 10.28 (1H, s), 10.58 (1H, s).

MASS (m/z): 412 (M⁺+1).

PREPARATION 230

To a solution of4-[N′-[4-(cis-2,6-dimethylmorpholin-4-yl)benzoyl]hydrazinocarbonyl]benzoicacid methyl ester (100 mg) in dimethoxyethane (3 ml) was addedphosphorus pentasulfide (82 mg). The mixture was refluxed for 5 hours.After cooling to ambient temperature, the reaction mixture was pouredinto cold water and the mixture was adjusted to pH 11 with 1N-sodiumhydroxide aqueous solution. The resulting precipitates were filtered,washed with water and dried to give4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoicacid methyl ester (97.4 mg).

IR (KBr): 1716, 1605, 1437, 1412, 1277, 1238 cm⁻¹.

NMR (CDCl₃, δ): 1.29 (6H, d, J=6.2 Hz), 2.54 (2H, t, J=11.3 Hz), 3.61(2H, d, J=11.9 Hz), 3.7-3.9 (2H, m), 3.96 (3H, s), 6.96 (2H, d, J=8.9Hz), 7.91 (2H, d, J=8.8 Hz), 8.0-8.25 (4H, m).

MASS (m/z): 410 (M⁺+1).

PREPARATION 231

A mixture of4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoicacid methyl ester (527 mg) and 1.0 mol/l sodium hydroxide solution (2.6ml) in a mixed solvent of methanol (10 ml) and tetrahydrofuran (25 ml)was refluxed for 6 hours. After cooling to ambient temperature, thereaction mixture was poured into cold water and the mixture was adjustedwith 1.0 mol/l hydrochloric acid. The resulting precipitates werefiltered, washed with water and dried to give4-[5-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoicacid (429.1 mg).

IR (KBr): 1686, 1605, 1412, 1236 cm⁻¹.

NMR (DMSO-d₆, δ): 1.18 (6H, d, J=6.1 Hz), 2.39 (2H, t, J=11.2 Hz),3.6-3.9 (4H, m), 7.11 (2H, d, J=9.1 Hz), 7.87 (2H, d, J=8.8 Hz), 8.11(4H, s), 13.3 (1H, br s).

MASS (m/z): 396 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 2324-[5-[4-(cis-2,6-bimethylmorpholin-4-yl)phenyl][1,3,4]thiadiazol-2-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1780, 1603, 1441, 1414, 1230 cm⁻¹.

NMR (CDCl₃, δ): 1.3 (6H, d, J=6.2 Hz), 2.45-2.65 (2H, m), 3.55-3.95 (4H,m), 6.97 (2H, d, J=8.9 Hz), 7.4-7.7 (3H, m), 7.85-8.5 (7H, m).

MASS (m/z): 513 (M⁺+1).

PREPARATION 233

A mixture of cesium trichloride (5.0 g) in tetrahydrofuran (45 ml) wasstirred at room temperature for 6 hours. 1,4-Dioxaspiro[4.5]decan-8-one(1.4 g) was added to the solution and stirred at room temperature for 1hour. To the solution was added dropwise with stirringcyclohexylmagnesium chloride (2.0M solution in diethyl ether) (6.7 ml)at 0° C. The reaction mixture was quenched with 10% acetic acid aqueoussolution. Diethyl ether was added to the solution. The organic layer wastaken, washed with brine, sodium hydrogen carbonate solution, brine anddried over magnesium sulfate. The magnesium sulfate was filtered off,and the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel chromatography to give8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol (1.266 g).

NMR (CDCl₃, δ): 0.9-2.1 (19H, m), 3.85-4.05 (4H, m).

PREPARATION 234

To a solution of 8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol (1.143 g)and iodomethane (0.59 ml) in N,N-dimethylformamide (11 ml) was addedsodium hydride (60% dispersion in mineral oil) (342 mg) at 0° C. Thesolution was stirred for 9 hours at 0° C., during which periodadditional iodomethane (0.59 ml) and sodium hydride (60% dispersion inmineral oil) (344 mg) was added to the mixture. The reaction mixture wasadded to a mixture of water and dichloromethane. The organic layer waswashed with water. The organic layer was taken and dried over magnesiumsulfate. The magnesium sulfate was filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (ethyl acetate elution) to give8-cyclohexyl-8-methoxy-1,4-dioxaspiro[4.5]decane (1.201 g).

IR (NaCl): 1448, 1377, 1250 cm⁻¹.

NMR (CDCl₃, δ): 0.9-1.9 (19H, m), 3.11 (3H, s), 3.85-4.0 (4H, m).

MASS (m/z): 277 (M⁺+Na).

PREPARATION 235

A solution of 8-cyclohexyl-8-methoxy-1,4-dioxaspiro[4.5]decane (1.15 g)and acetic acid (40 ml) in water was stirred at 100° C. for 6 hours.After cooling to room temperature, the reaction mixture was added to amixture of sodium hydrogen carbonate solution and diethyl ether. Theorganic layer was taken, washed with sodium hydrogen carbonate solutionand dried over magnesium sulfate. The magnesium sulfate was filteredoff, and the filtrate was concentrated under reduced pressure to give1-methoxy-1,1′-bicyclohexane-4-one (1.018 g).

NMR (CDCl₃, δ): 0.8-2.7 (19H, m), 3.22 (3H, s).

MASS (m/z): 233 (M⁺+Na).

PREPARATION 236

To an ice cooled solution of ethyl 4-(piperazin-1-yl)benzoate (1.23 g)and 1-methoxy-1,1′-bicyclohexane-4-one (916 mg) in a mixed solvent ofmethanol (20 ml), tetrahydrofuran (15 ml) and acetic acid (0.74 ml) wasadded sodium cyanoborohydride (301 mg) in a stream of nitrogen. Themixture was stirred at this temperature for 1.5 hours and at roomtemperature for 7.5 hours. The reaction mixture was quenched withsaturated aqueous sodium hydrogen carbonate solution. Dichloromethanewas added to the solution. The organic layer was taken, washed withsodium hydrogen carbonate solution and dried over magnesium sulfate. Themagnesium sulfate was filtered off, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography (3:1 hexane-methanol elution) to give4-[4-(1-methoxy-1,1′-bicyclohexan-4-yl)piperazinyl]benzoic acid ethylester (801 mg).

IR (KBr): 1701, 1608, 1520 cm⁻¹.

NMR (CDCl₃, δ): 0.7-1.9 (22H, m), 2.1-2.4 (1H, m), 2.65-2.85 (4H, m),3.10 (3H, s), 3.25-3.4 (4H, m), 4.32 (2H, q, J=7.1 Hz), 6.86 (2H, d,J=8.8 Hz), 7.92 (2H, d, J=8.9 Hz).

MASS (m/z): 429 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 231.

PREPARATION 2374-[4-(1-Methoxy-1,1′-bicyclohexyl-4-yl)piperazin-1-yl]benzoic acid

IR (KBr): 1689, 1610, 1232, 1186 cm⁻¹.

MASS (m/z): 401 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 2384-[4-(1-Methoxy-1,1′-bicyclohexyl-4-yl)piperazinyl]benzoic acidbenzotriazol-1-yl ester

IR (KBr): 1782, 1603, 1522, 1232, 1186 cm⁻¹.

NMR (CDCl₃, δ): 0.7-2.1 (19H, m), 2.2-2.3 (1H, m), 2.7-2.9 (4H, m), 3.11(3H, s), 3.4-3.55 (4H, m), 6.94 (2H, d, J=9.1 Hz), 7.3-7.6 (3H, m),8.0-8.2 (3H, m).

MASS (m/z): 518 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 236.

PREPARATION 2394-[4-(1-Methoxy-1,1′-bicyclohexyl-4-yl)piperazinyl]benzoic acid ethylester

IR (KBr): 1703, 1606, 1518, 1450, 1282, 1238 cm⁻¹.

NMR (CDCl₃, δ): 0.7-2.3 (23H, m), 2.55-2.7 (4H, m), 3.14 (3H, s),3.25-3.45 (4H, m), 4.33 (2H, q, J=7.1 Hz), 6.8-6.95 (2H, m), 7.85-8.05(2H, m).

MASS (m/z): 429 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 231.

PREPARATION 2404-[4-(1-Methoxy-1,1′-bicyclohexyl-4-yl)piperazinyl]benzoic acid

IR (KBr): 1668, 1603, 1228, 1186cm⁻¹.

MASS (m/z): 401 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 2414-[4-(1-Methoxy-1,1′-bicyclohexyl-4-yl)piperazin-1-yl]benzoic acidbenzotriazol-1-yl ester

IR (KBr): 1767, 1603, 1524, 1232, 1186 cm⁻¹.

NMR (CDCl₃, δ): 0.7-2.1 (19H, m), 2.15-2.3 (1H, m), 2.55-2.7 (4H, m),3.15 (3H, s), 3.35-3.55 (4H, m), 6.95 (2H, d, J=9.1 Hz), 7.35-7.6 (3H,m), 8.0-8.2 (3H, m).

MASS (m/z): 518 (M⁺+1).

PREPARATION 242

A solution of piperazine (30.37 g), 4-fluorobenzoic acid ethyl ester (20g) and potassium carbonate (65.75 g) in dimethylsulfoxide (100 ml) wasstirred for 5.5 hours at 150° C. After cooling to the room temperature,water was added to the solution. The resulting precipitate was collectedby filtration and dried to give ethyl 4-piperazinylbenzoate (18.48 g).

NMR (CDCl₃, δ): 1.37 (3H, t, J=7.1 Hz), 2.95-3.1 (4H, m), 3.2-3.4 (4H,m), 4.33 (2H, q, J=7.1 Hz), 6.87 (2H, d, J=9.0 Hz), 7.85-8.0 (2H, m).

MASS (m/z): 235 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 236.

PREPARATION 243 4-[4-(4-tert-Butylcyclohexyl)piperazinyl]benzoic acidethyl ester

IR (KBr): 1699, 1606, 1282, 1234, 1190 cm⁻¹.

NMR (CDCl₃, δ): 0.85 (9H, s), 0.9-1.45 (8H, m), 1.75-2.05 (4H, m),2.1-2.4 (1H, m), 2.71 (4H, t, J=5.1 Hz), 3.33 (4H, t, J=5.1 Hz),4.25-4.4 (2H, m), 6.86 (2H, d, J=9.0 Hz), 7.85-8.0 (2H, m).

MASS (m/z): 373 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 231.

PREPARATION 244 4-[4-(4-tert-Butylcyclohexyl)piperazinyl]benzoic acid

IR (KBr): 1680, 1603 cm⁻¹.

MASS (m/z): 345 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 245 4-4-(4-tert-Butylcyclohexyl)piperazinyl]benzoic acidbenzotriazol-1-yl ester

IR (KBr): 1788, 1593, 1232 cm⁻¹.

NMR (CDCl₃, δ): 0.86 (9H, s), 0.9-1.4 (5H, m), 1.7-2.4 (5H, m), 2.75(4H, t, J=5.0 Hz), 3.47 (4H, t, J=5.1 Hz), 6.8-7.05 (2H, m), 7.35-7.6(3H, m), 8.0-8.25 (3H, m).

MASS (m/z): 462 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 236.

PREPARATION 246 4-[4-(4-tert-Butylcyclohexyl)piperazinyl]benzoic acidethyl ester

IR (KBr): 1701, 1606, 1282, 1248, 1192 cm⁻¹.

NMR (CDCl₃, δ): 0.84 (9H, s), 1.0-1.5 (10H, m), 1.9-2.25 (3H, m), 2.58(4H, t, J=5.1 Hz), 3.31 (4H, t, J=5.1 Hz), 4.33 (2H, q, J=7.1 Hz),6.8-6.95 (2H, m), 7.85-8.0 (2H, m).

MASS (m/z): 373 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 231.

PREPARATION 247 4-[4-(4-tert-Butylcyclohexyl)piperazinyl]benzoic acid

IR (KBr): 1664, 1606, 1240 cm⁻¹.

MASS (m/z): 345 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 248 4-[4-(4-tert-Butylcyclohexyl)piperazinyl]benzoic acidbenzotriazol-1-yl ester

IR (KBr): 1778, 1603, 1232 cm⁻¹.

NMR (DMSO-d₆, δ): 0.86 (9H, s), 1.0-1.5 (7H, m), 1.95-2.3 (3H, m), 2.62(4H, t, J=5.1 Hz), 3.45 (4H, t, J=5.1 Hz), 6.95 (2H, d, J=9.2 Hz),7.35-7.6 (3H, m), 8.05-8.2 (3H, m).

MASS (m/z): 462 (M⁺+1).

PREPARATION 249

A mixture of 4-bromo-4′-hydroxy-1,1′-biphenyl (5 g),cis-2,6-dimethylmorpholine,dichlorobis(tri-o-tolylphosphine)-palladium(II) and lithiumbis(trimethylsilyl)amide (1.0 M solution in hexanes) (44 ml) in toluene(25 ml) was stirred for 6 hours at 100° C. The reaction mixture wasadded to a mixture of 1.0 mol/l hydrochloric acid and dichloromethane.The organic layer was washed with 1.0 mol/l hydrochloric acid, sodiumhydrogen carbonate solution and sodium chloride solution. The organiclayer was taken and dried over magnesium sulfate. The magnesium sulfatewas filtered off, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography (50:1dichloromethane-methanol elution) to give4′-(cis-2,6-dimethylmorpholin-4-yl)-1,1′-biphenyl-4-ol (1.49 g).

NMR (CDCl₃, δ): 1.28 (6H, d, J=6.3 Hz), 2.45 (2H, t, J=11.2 Hz), 3.49(2H, d, J=10.6 Hz), 3.75-3.95 (2H, m), 4.89 (1H, s), 6.8-7.0 (4H, m),7.4-7.5 (4H, m).

MASS (m/z): 284 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 218.

PREPARATION 250 Trifluoromethanesulfonic acid4′-(cis-2,6-dimethylmorpholin-4-yl)-1,1′-biphenyl-4-yl ester

NMR (CDCl₃, δ): 1.28 (6H, d, J=6.3 Hz), 2.47 (2H, t, J=11.3 Hz), 3.52(2H, d, J=10.4 Hz), 3.7-3.95 (2H, m), 6.98 (2H, d, J=8.8 Hz), 7.30 (2H,d, J=8.8 Hz), 7.48 (2H, d, J=8.7 Hz), 7.60 (2H, d, J=8.8 Hz).

MASS (m/z): 416 (M⁺+1).

PREPARATION 251

To a mixture of cesium carbonate (1.43 g), palladium(II) acetate (35 mg)and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (146 mg) in dioxane (6ml) was successively added trifluoromethanesulfonic acid4′-(cis-2,6-dimethylmorpholin-4-yl)-1,1′-biphenyl-4-yl ester (1.30 g)and ethyl 4-piperazinylbenzoate (0.88 g) in a stream of nitrogen. Themixture was stirred at ambient temperature for 30 minutes and at 100° C.for further 6.5 hours. After cooling to room temperature, water wasadded to the reaction mixture. The resulting precipitates were filtered,washed with water and dried. The residue was pulverized with acetone andcollected by filtration to give4-[4-[4′-(cis-2,6-dimethylmorpholin-4-yl)-1,1′-biphenyl-4-yl]piperazinyl]benzoicacid ethyl ester (1.17 g).

IR (KBr): 1703, 1608, 1504, 1284, 1230 cm⁻¹.

NMR (CDCl₃, δ): 1.28 (6H, d, J=6.3 Hz), 1.38 (3H, t, J=7.1 Hz), 2.45(2H, t, J=10.9 Hz), 3.3-3.6 (10H, m), 3.7-3.95 (2H, m), 4.34 (2H, q,J=7.1 Hz), 6.85-7.1 (6H, m), 7.45-7.6 (4H, m), 7.96 (2H, d, J=8.9 Hz).

MASS (m/z): 500 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 222.

PREPARATION 2524-[4-[4′-(cis-2,6-Dimethylmorpholin-4-yl)-1,1′-biphenyl-4-yl]piperazinyl]benzoicacid

IR (KBr): 1668, 1603, 1504, 1230 cm⁻¹.

MASS (m/z): 472 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 2534-[4-[4′-(cis-2,6-Dimethylmorpholin-4-yl)-1,1′-biphenyl-4-yl]piperazinyl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1765, 1601, 1502, 1230, 1184 cm⁻¹.

NMR (CDCl₃, δ): 1.28 (6H, d, J=6.3 Hz), 2.45 (2H, t, J=11.2 Hz),3.35-3.95 (12H, m), 6.9-7.1 (6H, m), 7.4-7.6 (7H, m), 8.05-8.2 (3H, m).

MASS (m/z): 589 (M⁺+1).

PREPARATION 254

A solution of 4-bromophenol (3 g) and 1,4-dibromobutane (6.2 ml) inN,N-dimethylformamide (30 ml) was treated with potassium carbonate (2.89g) at room temperature for 27 hours. The mixture was diluted with ethylacetate and washed with brine. The organic layer was dried overmagnesium sulfate, filtered, and evaporated. The residue was purified bysilica gel chromatography (25:1 hexane-ethyl acetate elution) to give1-bromo-4-(4-bromobutoxy)benzene (3.09 g).

NMR (CDCl₃, δ): 1.8-2.15 (4H, m), 3.48 (2H, t, J=6.4 Hz), 3.96 (2H, t,J=5.9 Hz), 6.7-6.85 (2H, m), 7.3-7.45 (2H, m).

PREPARATION 255

A solution of 1-bromo-4-(4-bromobutoxy)benzene (3.05 g) in methanol (30ml) was treated with 28% sodium methoxide in methanol (2.43 ml), and thesolution was refluxed for 5 hours. After cooling, the reaction mixturewas added to a mixture of water and ethyl acetate. The organic layer waswashed with brine. The organic layer was taken and dried over magnesiumsulfate. The magnesium sulfate was filtered off, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography (10:1 hexane-ethyl acetate elution) to give1-bromo-4-(4-methoxybutoxy)benzene (1.95 g).

IR (NaCl): 1591, 1489, 1286, 1244 cm⁻¹.

NMR (CDCl₃, δ): 1.65-1.95 (4H, m), 3.35 (3H, s), 3.44 (2H, t, J=6.1 Hz),3.95 (2H, t, J=6.1 Hz), 6.77 (2H, d, J=8.9 Hz), 7.36 (2H, d, J=8.9 Hz).

MASS (m/z): 282 (M⁺+Na).

PREPARATION 256

To the solution of 1-bromo-4-(4-methoxybutoxy)benzene (4.94 g) andmagnesium (463 mg) in tetrahydrofuran (50 ml) was added iodine at roomtemperature. The solution was refluxed for 7.5 hours, during whichperiod diiodoethane was added to the mixture. After cooling to 0° C.,4-[4-(4-oxopiperidin-1-yl)phenyl]piperazine-1-carboxylic acid benzylester (4.94 g) in tetrahydrofuran (20 ml) was added dropwise withstirring to the solution. The mixture was stirred at room temperaturefor 2 hours. The reaction mixture was added to a mixture of ammoniumchloride solution and ethyl acetate. The organic layer was taken, washedwith brine, sodium hydrogen carbonate solution and brine and dried overmagnesium sulfate. The magnesium sulfate was filtered off, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (50:1 dichloromethane-methanolelution) to give4-[4-[4-hydroxy-4-[4-(4-methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazine-1-carboxylicacid benzyl ester (3.42 g).

NMR (CDCl₃, δ): 1.65-2.0 (6H, m), 2.1-2.4 (2H, m), 2.95-3.3 (6H, m),3.35 (3H, s), 3.35-3.75 (8H, m), 3.99 (2H, t, J=5.9 Hz), 5.16 (2H, s),6.8-7.05 (6H, m), 7.3-7.5 (9H, m).

MASS (m/z): 574 (M⁺+1).

PREPARATION 257

To a solution of4-[4-[4-hydroxy-4-[4-(4-methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazine-1-carboxylicacid benzyl ester (3.41 g) in dichloromethane (50 ml) was addedtrifluoroacetic acid (8.5 ml) at 0° C. The reaction mixture was stirredat 0° C. for 1 hour and at room temperature for further 6 hours. To thereaction mixture was added 1 mol/ml sodium hydroxide solution (170 ml),dichloromethane (136 ml) and methanol (14 ml). The organic layer waswashed with water and brine, dried over magnesium sulfate, filtered, andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography (50:1 dichloromethane-methanolelution) to give4-[4-[4-[4-(4-methoxybutoxy)phenyl]-3,6-dihydro-2H-pyridin-1-yl]phenyl]piperazine-1-carboxylicacid benzyl ester (2.23 g).

IR (KBr): 1701, 1514, 1232 cm⁻¹.

NMR (CDCl₃, δ): 1.7-2.0 (4H, m), 2.65 (2H, br s), 2.95-3.15 (4H, m),3.35 (3H, s), 3.35-3.9 (10H, m), 3.99 (2H, t, J=6.0 Hz), 5.16 (2H, s),6.18 (1H, m), 6.8-7.0 (6H, m), 7.3-7.45 (7H, m).

MASS (m/z): 556 (M⁺+1).

PREPARATION 258

To a mixture of4-[4-[4-[4-(4-methoxybutoxy)phenyl]-3,6-dihydro-2H-pyridin-1-yl]phenyl]piperazine-1-carboxylicacid benzyl ester (2.20 g) and ammonium formate (1.25 g) in 90% methanol(44 ml) and dioxane was added 10% palladium on carbon at roomtemperature. The reaction mixture was heated at 100° C. for 2 hours.After cooling, the reaction mixture was filtered and evaporated. Sodiumhydrogen carbonate solution was added to the residue. And the resultingprecipitate was collected by filtration, washed with water and driedunder hi-vacuum to give1-[4-[4-[4-(4-methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazine(1.36 g).

IR (KBr): 1514, 1234 cm⁻¹.

NMR (DMSO-d₆, δ): 1.5-1.9 (8H, m), 2.5-3.0 (7H, m), 3.23 (3H, s),3.1-4.1 (11H, m), 6.8-7.25 (5H, m).

MASS (m/z): 424 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 221.

PREPARATION 2594-[4-[4-[4-[4-(4-Methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazin-1-yl]benzoicacid methyl ester

IR (KBr): 1711, 1606, 1514, 1282, 1227 cm⁻¹.

NMR (CDCl₃, δ): 1.38 (3H, t, J=7.1 Hz), 1.65-2.0 (8H, m), 2.5-2.9 (3H,m), 3.5-3.8 (12H, m), 3.35 (3H, s), 3.97 (2H, t, J=6.0 Hz), 4.34 (2H, q,J=7.0 Hz), 6.8-7.2 (10H, m), 7.95 (2H, d, J=8.8 Hz).

MASS (m/z): 572 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 222.

PREPARATION 2604-[4-[4-[4-[4-(4-Methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazin-1-yl]benzoicacid

IR (KBr): 1514, 1228 cm⁻¹.

MASS (m/z): 544 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 2614-[4-[4-[4-[4-(4-Methoxybutoxy)phenyl]piperidin-1-yl]phenyl]piperazin-1-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1514, 1230 cm⁻¹.

NMR (CDCl₃, δ): 1.6-2.0 (8H, m), 2.5-2.9 (3H, m), 3.2-3.8 (15H, m),3.9-4.05 (2H, m), 6.8-7.3 (10H, m), 7.35-7.6 (3H, m), 8.05-8.25 (3H, m).

MASS (m/z): 661 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 219.

PREPARATION 2621-[4-[4-[4-(6-Methoxyhexylthio)piperidin-1-yl]phenyl]piperazin-1-yl]ethanone

IR (KBr): 1622, 1516, 1448, 1242 cm⁻¹.

NMR (CDCl₃, δ): 1.3-1.9 (10H, m), 1.95-2.15 (5H, m), 2.57 (2H, t, J=7.3Hz), 2.6-2.85 (3H, m), 2.95-3.15 (4H, m), 3.25-3.85 (11H, m), 6.89 (4H,s).

MASS (m/z): 434 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 220.

PREPARATION 2631-[4-[4-(6-Methoxyhexylthio)piperidin-1-yl]phenyl]piperazine

IR (KBr): 1622, 1514, 1454, 1242, 1120 cm⁻¹.

NMR (CDCl₃, δ): 1.3-1.9 (10H, m), 1.95-2.15 (2H, m), 2.57 (2H, t, J=7.3Hz), 2.6-2.85 (3H, m), 3.04 (8H, s), 3.3-3.6 (7H, m), 6.89 (4H, s).

MASS (m/z): 392 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 221.

PREPARATION 2644-[4-[4-[4-(6-Methoxyhexylthio)piperidin-1-yl]phenyl]piperazin-1-yl]benzoicacid ethyl ester

NMR (CDCl₃, δ): 1.3-1.9 (13H, m), 1.95-2.15 (2H, m), 2.57 (2H, t, J=7.3Hz), 2.6-2.85 (3H, m), 3.15-3.6 (15H, m), 4.34 (2H, q, J=7.0 Hz),6.85-7.0 (6H, m), 7.95 (2H, d, J=8.8 Hz).

MASS (m/z): 540 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 222.

PREPARATION 2654-[4-[4-[4-(6-Methoxyhexylthio)piperidin-1-yl]phenyl]piperazin-1-yl]benzoicacid

IR (KBr): 1605, 1587, 1546, 1514, 1408, 1225 cm⁻¹.

MASS (m/z): 512 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 2664-[4-[4-[4-(6-Methoxyhexylthio)piperidin-1-yl]phenyl]piperazin-1-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1782, 1601, 1514, 1446, 1230, 1184 cm⁻¹.

NMR (CDCl₃, δ): 1.3-1.9 (10H, m), 1.95-2.15 (2H, m), 2.58 (2H, t, J=7.3Hz), 2.65-2.85 (3H, m), 3.15-3.7 (15H, m), 6.85-7.1 (6H, m), 7.35-7.6(3H, m), 8.05-8.2 (3H, m).

MASS (m/z): 629 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 254.

PREPARATION 267 4-(4-Bromobutoxy)benzonitrile

IR (KBr): 2222, 1605, 1506, 1302, 1252 cm⁻¹.

NMR (CDCl₃, δ): 1.9-2.2 (4H, m), 3.49 (2H, t, J=6.2 Hz), 4.05 (2H, t,J=5.7 Hz), 6.85-7.0 (2H, m), 7.5-7.65 (2H, m).

MASS (m/z): 254 (M⁺).

The following compound was obtained according to a similar manner tothat of Preparation 256.

PREPARATION 268 4-(4-Methoxybutoxy)benzonitrile

IR (KBr): 2216, 1605, 1570, 1510, 1468, 1308, 1261 cm⁻¹.

NMR (CDCl₃, δ): 1.65-2.0 (4H, m), 3.35 (3H, s), 3.44 (2H, t, J=6.1 Hz),4.00 (2H, t, J=6.2 Hz), 6.85-7.0 (2H, m), 7.5-7.65 (2H, m).

MASS (m/z): 206 (M⁺+1).

PREPARATION 269

To a solution of 4-(4-methoxybutoxy)benzonitrile (21.8 g) andtrifluoroacetic acid (109 ml) in toluene (218 ml) was addedthiosemicarbazide (11.62 g). The solution was stirred for 31 hours at60° C., during which period additional thiosemicarbazide (2.90 g) andtrifluoroacetic acid was added to the mixture. The reaction mixture waspulverized with ethyl acetate. The precipitate was collected byfiltration and dried to give5-[4-(4-methoxybutoxy)phenyl][1,3,4]thiadiazol-2-ylamine trifluoroaceticacid salt (15.10 g).

IR (KBr): 1674, 1606, 1400 cm⁻¹.

NMR (CDCl₃, δ): 1.55-2.0 (4H, m), 3.36 (3H, s), 3.45 (2H, t, J=6.0 Hz),4.04 (2H, t, J=6.1 Hz), 4.41 (4H, br s), 6.95 (2H, d, J=8.7 Hz), 7.63(2H, d, J=8.7 Hz).

MASS (m/z): 280.

PREPARATION 270

To a suspension ofS-[4-(4-methoxybutoxy)phenyl][1,3,4]thiadiazol-2-ylamine trifluoroaceticacid salt (45.00 g) in ethanol (450 ml) was added ethyl4-bromoacetylbenzoate (28.85 g), and the mixture was stirred underreflux for 4 hours. The reaction mixture was pulverized with ethylacetate. The precipitate was collected by filtration and dried. To asuspension of the powder in xylene (450 ml) was added trifluoroaceticacid (67.5 ml), and the mixture was stirred at 130° C. for 4 hours. Thereaction mixture was pulverized with diisopropyl ether. The precipitatewas collected by filtration and dried. The residue was pulverized withethyl acetate, and the precipitate was collected by filtration and driedto give4-[2-[4-(4-methoxybutoxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid ethyl ester (29.85 g).

NMR (CDCl₃, δ): 1.41 (3H, t, J=7.1 Hz), 1.65-2.0 (4H, m), 3.36 (3H, s),3.4-3.55 (2H, m), 4.0-4.15 (2H, m), 4.39 (2H, q, J=7.1 Hz), 6.99 (2H, d,J=8.8 Hz), 7.55-8.15 (7H, m).

MASS (m/z): 452 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 231.

PREPARATION 2714-[2-[4-(4-Methoxybutoxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid

IR (KBr): 1680, 1608, 1591, 1549, 1468, 1404, 1257 cm⁻¹.

NMR (DMSO-d₆, δ): 1.55-1.9 (4H, m), 3.24 (3H, s), 3.3-3.5 (2H, m), 4.10(2H, t, J=5.9 Hz), 7.14 (2H, d, J=8.7 Hz), 7.8-8.05 (6H, m), 8.84 (1H,s).

MASS (m/z): 424 (M⁺+1).

The following compound was obtained according to a similar manner tothat of Preparation 223.

PREPARATION 2724-[2-[4-[4-Methoxybutoxy)phenyl]imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoicacid benzotriazol-1-yl ester

IR (KBr): 1768, 1606, 1547, 1470, 1404, 1255, 1176 cm⁻¹.

NMR (CDCl₃, δ): 1.6-2.0 (4H, m), 3.37 (3H, s), 3.47 (3H, t, J=6.0 Hz),4.08 (3H, t, J=6.1 Hz), 7.02 (2H, d, J=8.7 Hz), 7.4-7.65 (3H, m),7.7-8.4 (8H, m).

MASS (m/z): 541 (M⁺+1).

PREPARATION 273

A solution of oxalyl dichloride (597 μl) in dry dichloromethane (7 ml)was cooled to −70° C. in nitrogen atmosphere, and a solution ofdimethylsulfoxide (1.15 ml) in dry dichloromethane (1.5 ml) was addedslowly and stirred for 30 minutes at −70° C. To the reaction mixture wasadded a solution of (3-hydroxypropyl)carbamic acid tert-butyl ester (1.0g) in dry dichloromethane (7 ml) slowly to maintain the reactiontemperature at −60° C. and stirred for 30 minutes at −70° C. To thereaction mixture was added triethylamine (3.98 ml) slowly to maintainthe reaction temperature at −60° C. Then the reaction mixture wasallowed to warm to room temperature. To the reaction mixture was addedwater (10 ml) and stirred for 10 minutes, then the organic layer wasseparated. The aqueous layer was extracted with dichloromethane (50ml×2). The organic layer was combined and washed with brine, dried overmagnesium sulfate. Magnesium sulfate was filtered off, and the filtratewas evaporated under reduced pressure to give3-tert-butoxycarbonylaminopropionaldehyde (1.28 g), that was used crudein the next reaction.

The following compound was obtained according to a similar manner tothat of Preparation 273.

PREPARATION 274

5-tert-Butoxycarbonylaminovaleraldehyde, that was used crude in the nextreaction.

The following compound was obtained according to a similar manner tothat of Preparation 273.

PREPARATION 275

6-tert-Butoxycarbonylaminohexanaldehyde, that was used crude in the nextreaction.

The following compound was obtained according to a similar manner tothat of Preparation 273.

PREPARATION 276

4-tert-Butoxycarbonylaminobutylaldehyde, that was used crude in the nextreaction.

PREPARATION 277

To an ice-cooled solution of 5-aminopentan-1-ol (5.0 g) in water (40 ml)and acetone (40 ml) was added triethylamine (8.78 g) and di-tert-butyldicarbonate (13.75 g), then the solution was stirred at 30° C. for 3hours. The solvent was evaporated under reduced pressure and extractedwith ethyl acetate. The organic layer was washed with water and brine,then dried over magnesium sulfate. Magnesium sulfate was filtered off,and the filtrate was evaporated under reduced pressure to give a crudeyellow oil (12.7 g). The crude oil was purified by silica gelchromatography (50:1-4:1 dichloromethane-methanol) to give5-hydroxypentylcarbamic acid tert-butyl ester (8.68 g), as a pale yellowoil.

IR (KBr): 3344.0, 2975.6, 2935.1, 2665.7, 1706.7, 1695.1, 1529.3,1280.5, 1249.6, 1178.3, 1168.7 cm⁻¹.

NMR (DMSO-d₆, δ): 1.1-1.6 (15H, m), 2.88 (2H, dd, J=6.5 and 12.6 Hz),3.2-3.5 (2H, m), 4.33 (1H, t, J=5.1 Hz), 6.75 (1H, m).

The following compound was obtained according to a similar manner tothat of Preparation 277.

PREPARATION 278 6-Hydroxyhexylcarbamic acid tert-butyl ester

IR (KBr): 3351.7, 2977.6, 2937.1, 2859.9, 1714.4, 1679.7, 1533.1,1276.6, 1249.6, 1180.2, 1164.8 cm⁻¹.

NMR (DMSO-d₆, δ): 1.0-1.6 (17H, m), 4.83 (2H, dd, J=6.5 and 12.8 Hz),3.2-3.59 (2H, m), 4.32 (1H, t, J=5.2 Hz), 6.75 (1H, m).

The following compound was obtained according to a similar manner tothat of Preparation 277.

PREPARATION 279 (S)-(−)-4-tert-Butoxycarbonylamino-2-hydroxybutyric acid

NMR (DMSO-d₆, δ): 1.37 (9H, s), 1.4-1.9 (2H, m), 3.00 (2H, dd, J=7.0 and13.3 Hz), 3.92 (1H, dd, J=4.0 and 8.4 Hz), 6.78 (1H, m).

PREPARATION 280

To a solution of pyridinium chlorochromate (2.0 g) in dichloromethane(15 ml) was added a solution of 6-hydroxyhexanoic acid ethyl ester (1.0g) in dichloromethane (1.5 ml) in one portion and stirred for 1.5 hoursat ambient temperature. Ether (15 ml) was added to the reaction mixture,and the insoluble material removed by filtration and discarded. Thefiltrate was purified by silica gel chromatography (diethyl ether) togive 6-oxohexanoic acid ethyl ester (884.6 mg), as a pale green oil.

IR (KBr): 2981.4, 2940.9, 2871.5, 2827.1, 2723.0, 1731.8, 1184.1 cm⁻¹.

NMR (CDCl₃, δ): 1.26 (3H, t, J=7.1 Hz), 1.5-1.8 (4H, m), 2.2-2.6 (4H,m), 4.13 (2H, q, J=7.1 Hz), 9.77 (1H, t, J=1.6 Hz).

The following compound was obtained according to a similar manner tothat of Preparation 280.

PREPARATION 281 9-Oxo-nonanic acid methyl ester

IR (KBr): 2933.2, 2858.0, 2721.1, 1743.3, 1724.0, 1538.6, 1245.8,1199.5, 1172.5 cm⁻¹.

NMR (CDCl₃, δ): 1.24 (6H, s), 1.3-1.7 (4H, m), 2.18 (2H, t, J=7.3 Hz),2.29 (2H, t, J=7.3 Hz), 3.58 (3H, s), 11.97 (1H, s).

PREPARATION 282

A solution of N-t-butoxycarbonyl-L-glutamic acid α-t-butyl ester (600mg) and 4-piperidone hydrochloride monohydrate (455.6 mg) indichloromethane (6 ml)-DMF (6 ml), was treated with1-hydroxybenzotriazole (294 mg) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (460.5 mg) and stirred 15hours at room temperature. The reaction was diluted with ethyl acetateand washed with water, dried over magnesium sulfate, evaporated, and theresidue was purified by silica gel column chromatography (EtOAc elution)to give 4-(4-piperidon-1-yl)carbonyl-2-tert-butoxycarbonylaminobutanoicacid tert-butyl ester (450 mg) as a white solid.

IR (KBr): 3381, 2931, 2883, 1707, 1631.5, 1510, 1448, 1367, 1321 cm⁻¹.

NMR (CDCl₃, δ): 1.43 (9H, s), 1.48 (9H, s), 1.85-2.10 (1H, m), 2.15-2.4(1H, m), 2.4-2.6 (6H, m), 3.6-4.1 (4H, m), 4.1-4.3 (1H, m), 5.19 (1H, brd, J=8.4 Hz).

The following compound was obtained according to a similar manner tothat of Preparation 282.

PREPARATION 2831-(1-tert-Butoxycarbonylazetidin-3-yl)carbonyl-4-piperidone

IR (KBr): 2979.5, 2891, 1712.5, 1691.3, 1649 cm⁻¹.

NMR (CDCl₃, δ): 1.44 (9H, s), 2.44-2.53 (4H, m), 3.54-3.61 (3H, m),3.89-3.95 (2H, m), 4.06-4.22 (4H, m).

MASS (m/z): 305.2 (M⁺+Na).

Elemental Analysis Calcd. for C₁₄H₂₂N₂O₄.0.6H₂O: C, 57.36, H, 7.98, N,9.56. Found: C, 57.29, H, 7.65, N, 9.58.

PREPARATION 284

To a solution of 1,3-dioxy-5-hydroxymethyl-4-methyl-2-oxo-4-cyclopentene(2 g) and N,N′-disuccinimidyl carbonate (4.33 g) in dimethylformamide(10 ml) was added pyridine (1.37 ml) and stirred at ambient temperature.The reaction mixture was added to a mixture of water and ethyl acetate.The organic layer was taken and dried over magnesium sulfate. Themagnesium sulfate was filtered off, and the filtrate was evaporatedunder reduced pressure to give(1,3-dioxy-2-oxo-4-cyclopenten-5-yl)methoxycarbonyloxysuccinimido (2.477g).

IR (KBr): 1808.8, 1785.8, 1741.4, 1733.7, 1259.3, 1228.4, 1209.1 cm⁻¹.

NMR (CDCl₃, δ): 2.20 (3H, s), 2.86 (4H, s), 5.06 (2H, s).

ESI-MASS (m/z): 294.1 (M⁺+Na+1).

PREPARATION 285

To a solution of 1-methyl-4-piperidone (1.0 g) in N,N-dimethylformamide(10 ml) was added 2-iodoethanol (0.70 ml-1.5 g) and stirred overnight atambient temperature. The reaction mixture was evaporated under reducedpressure and washed by ethyl acetate to afford1-(2-hydroxyethyl)-1-methyl-4-oxopiperidinium iodide (0.94 g).

MASS (m/z): 158 (M⁺−I⁻).

PREPARATION 286

To a solution of 1-methyl-4-piperidone (1.0 g) in dichloromethane (5 ml)was slowly added iodomethane (1 ml) at 0° C. and stirred for 30 minutesat ambient temperature. To the reaction mixture was added isopropylether (10 ml), and the resulting precipitate was collected by filtrationto give 1,1-dimethyl-4-oxopiperidinium iodide (1.416 g).

NMR (DMSO-d₆, δ): 1.87 (2H, t, J=5.4 Hz), 2.71 (2H, t, J=6.4 Hz), 3.09(3H, s), 3.27 (3H, s), 3.30-3.40 (2H, m), 3.75 (2H, t, J=6.6 Hz).

The Starting Compounds (287) to (290) used and the Object Compounds(287) to (290) obtained in the following Preparations 287 to 20 aregiven in the table as below, in which the formulas of the startingcompounds are in the upper column and the formulas of the objectcompounds are in the lower column, respectively.

Prepara- tion No. Formula 287

288

289

290

The following compounds [Preparations 287 to 290] were obtainedaccording to a similar manner to that of Preparation

PREPARATION 287

MASS (m/z): 1317.3 (M⁺−Na).

PREPARATION 288

MASS (m/z): 1302.3 (M⁺−Na).

PREPARATION 289

MASS (m/z): 1320.3 (M⁺−Na).

PREPARATION 290

The object compound was used directly in the next reaction withoutpurification.

The Starting Compounds (291) to (338) used and the Object Compounds(291) to (338) obtained in the following Preparation 291 to 338 aregiven in the table as below, in which the formulas of the startingcompounds are in the upper column and the formulas of the objectcompounds are in the lower column, respectively.

Prepar- ation No. Formula 291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

The following compounds [Preparations 291 to 338] were obtainedaccording to a similar manner to that of Preparation 10.

PREPARATION 291

MASS (m/z): 1283.3 (M⁺−Na).

PREPARATION 292

MASS (m/z): 1338.3 (M⁺−Na).

PREPARATION 293

MASS (m/z): 1313.2 (M⁺−Na).

PREPARATION 294

MASS (m/z): 1329.3 (M⁺−Na).

PREPARATION 295

MASS (m/z): 1321.5 (M⁺−Na).

PREPARATION 296

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 297

MASS (m/z): 1320-4 (M⁺−Na).

PREPARATION 298

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 299

IR (KBr): 1605, 1444 cm⁻¹.

MASS (m/z): 1372 (M−2).

PREPARATION 300

MASS (m/z): 1232.2 (M⁺−Na).

PREPARATION 301

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 302

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 303

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 304

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 305

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 306

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 307

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 308

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 309

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 310

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 311

MASS (m/z): 1361 (M⁺+23).

PREPARATION 312

MASS (m/z): 1308 (M⁺−23).

PREPARATION 313

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 314

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 315

MASS (m/z): 1304.3 (M⁺−Na).

PREPARATION 316

IR (KBr): 3345.9, 1633.4, 1511.9, 1232.3 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.8 Hz), 1.08 (3H, d, J=6.1 Hz),1.23-1.26 (2H, m), 2.80-5.21 (51H, m), 6.66-8.72 (20H, m).

MASS (m/z): 1372.3 (M⁺−Na).

PREPARATION 317

IR (KBr): 3336.2, 1631.5, 1510.0, 1230.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=7.1 Hz), 1.08 (3H, d, J=5.8 Hz),1.24-5.21 (50H, m), 6.68-8.72 (22H, m).

MASS (m/z): 1308.4 (M⁺−Na).

PREPARATION 318

MASS (m/z): 1262 (M⁺−23).

PREPARATION 319

MASS (m/z): 1262 (M⁺−23).

PREPARATION 320

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 321

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 322

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 323

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 324

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 325

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 326

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 327

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 328

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 329

The object compound was used directly in the next reaction withoutpurification.

PREPARATION 330

IR (KBr): 3351.7, 2256.3, 1633.4, 1232.3, 1116.6 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.08 (3H, d, J=5.9 Hz),1.80-5.20 (52H, m), 5.91-5.94 (1H, m), 6.68-8.72 (21H, m).

MASS (m/z): 1338.4 (M⁺−Na).

PREPARATION 331

IR (KBr): 2256.3, 1633.4, 1510.0, 1085.7 cm⁻¹.

NMR (DMSO-d₆, δ): 0.94-5.93 (68H, m), 6.69-8.72 (16H, m).

MASS (m/z): 1330.5 (M⁺−Na).

PREPARATION 332

IR (KBr): 3351.7, 2256.3, 1666.2, 1633.4, 1230.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.81-5.20 (74H, m), 5.88-5.91 (1H, m), 6.68-8.72 (12H,m).

PREPARATION 333

IR (KBr): 2256.3, 1633.4, 1510.0, 1322.9, 1232.3 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.6 Hz),1.24-5.20 (57H, m), 5.89-5.93 (1H, m), 6.68-8.79 (16H, m).

MASS (m/z): 1286.3 (M⁺−Na).

PREPARATION 334

IR (KBr): 3349.7, 2256.3, 1633.4, 1232.3 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.08 (3H, d, J=5.5 Hz),1.70-5.21 (53H, m), 5.90-5.93 (1H, m), 6.68-8.72 (16H, m).

MASS (m/z): 1336.3 (M⁺+Na).

PREPARATION 335

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.6-2.0 (8H, m), 2.2-2.5 (3H, m), 2.7 (1H, m), 2.9 (2H, m), 3.23 (3H,s), 3.34 (2H, m), 3.74 (2H, m), 3.6-4.6 (15H, m), 4.85 (3H, m), 5.03(1H, d, J=6.2 Hz), 5.10 (1H, m), 5.20 (2H, m), 5.88 (1H, m), 6.71 (1H,d, J=8.2 Hz), 6.78 (1H, d, J=8.2 Hz), 6.98 (1H, s), 7.14 (2H, d, J=8.9Hz), 7.42 (1H, d, J=8.3 Hz), 7.51 (1H, d, J=9.3 Hz), 7.79 (1H, m), 7.90(2H, d, J=8.9 Hz), 7.97 (4H, s), 8.32 (1H, d, J=7.7 Hz), 8.51 (1H, d,J=7.5 Hz), 8.71 (1H, m), 8.84 (1H, s).

MASS (m/z): 1290.3 (M⁺+Na).

PREPARATION 336

MASS (m/z): 1318.3 (M⁺−Na).

PREPARATION 337

MASS (m/z): 1279.4 (M⁺−Na).

PREPARATION 338

MASS (m/z): 1231.4 (M⁺−Na).

The Starting Compounds (339) to (343) used and the Object Compounds(339) to (343) obtained in the following Preparations 339 to 343 aregiven in the table as below, in which the formulas of the startingcompounds are in the upper column and the formulas of the objectcompounds are in the lower column, respectively.

Preparation No. Formula 339

340

341

342

343

The following compound was obtained according to a similar manner tothat of Preparation 2.

PREPARATION 339

IR (KBr): 1666, 1633, 1516, 1443, 1279, 1254 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.94 (3H, d, J=6.74 Hz), 1.09 (3H, d, J=5.59 Hz),1.36 (9H, s), 1.50-2.00 (3H, m), 2.10-2.40 (3H, m), 2.55-3.40 (5H, m),3.55-4.50 (12H, m), 4.70-4.90 (2H, m), 6.73 (1H, d, J=8.20 Hz), 6.82(1H, d, J=9.80 Hz), 7.06 (1H, s).

ESI MASS (m/z) (Positive): 1047.2 (M⁺+Na).

Elemental Analysis Calcd. for C₄₀H₅₇N₈O₂₀SNa.5H₂O: C, 43.09, H, 6.06, N,10.05. Found: C, 43.05, H, 6.09, N, 9.98.

HPLC (20% CH₃CN-pH 6.86 standard buffer solution; YMC-ODS 150×4.6mm): LT5.38 min.

The following compound was obtained according to a similar manner tothat of Preparation 9.

PREPARATION 340

NMR (DMSO-d₆+D₂O, δ): 0.94 (3H, d, J=6.74 Hz), 1.14 (3H, d, J=5.89 Hz),1.30-1.55 (1H, m), 1.70-2.00 (1H, m), 2.05-2.45 (3H, m), 2.50-2.90 (3H,m), 3.05-3.35 (1H, m), 3.50-4.50 (16H, m), 4.65-4.95 (2H, m), 6.70-6.85(2H, m), 7.09 (1H, d, J=1.56 Hz).

ESI-MASS (m/z) (Positive): 925.2 (M⁺). HPLC (20% CH₃CN-pH 6.86 standardbuffer solution; YMC-ODS 150×4.6mm): LT 2.01 min.

The following compounds [Preparation 341 to 342] were obtained accordingto a similar manner to that of Preparation 2.

PREPARATION 341

IR (KBr): 3354, 2925.5, 2854, 2256, 1631.5, 1535, 1516, 1448, 1267,1246, 1084, 1047 cm⁻¹.

MASS (m/z): 1123.5 (M⁺−Na).

Elemental Analysis Calcd. for C₅₁H₇₉N₈O₁₈SNa.7H₂O: C, 48.10, H, 7.36, N,8.80. Found: C, 48.31, H, 7.26, N, 8.72.

The following compound was obtained according to a similar manner tothat of Preparation 2.

PREPARATION 342

IR (KBr): 2931, 1659, 1635, 1531, 1506, 1439, 1387, 1350 cm⁻¹.

MASS (m/z): 1133.4 (M⁺−Na).

PREPARATION 343

To a solution of Starting Compound (343) (1 g) in trifluoroacetic acid(20 ml) was added 1N HCl aq. (4 ml) and stirred for 7 hours at ambienttemperature. The reaction mixture was pulverized with water (90 ml). Theprecipitate was collected by filtration and dried under reducedpressure. The powder was added to 36% acetonitrile aq. (190 ml) andsubjected to column chromatography on ODS (YMC-gel ODS-AM X S-50)(Trademark: prepared by Yamamura Chemical Lab.) and eluted with 35%acetonitrile aq. The fractions containing the object compound werecombined and evaporated under reduced pressure to remove acetonitrile.The residue was lyophilized to give Object Compound (343) (319 mg).

IR (KBr): 3344.0, 2254, 1658.5, 1635.3, 1444.4, 1257.4 cm⁻¹.

ESI-MASS (m/z): 1213 (M⁺−1).

PREPARATION 344

Dimethylformamide (485 l), p-pentyloxyacetophenone (30.3 kg) anddimethyl terephthalate (45.6 kg) were charged in 2000-liter reactor andstirred. To this mixture was added potassium tert-butoxide (24.7 kg) inseveral portions and, after that, a reaction was carried out at theinner temperature of 20 to 25° C. for 3.5 hours. After completion of thereaction, methanol (1210 l) was added to the reaction solution at 20 to30° C. and then 6N hydrochloric acid (49 l) at 5 to 15° C. The mixturewas stirred at room temperature for 1 hour, and the resulting appearedcrystals were filtered and washed with methanol (152 l) and then water(152 l). The crystals were dried overnight in vacuo to give1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (49.6kg).

NMR (CDCl₃, δ): 0.95 (3H, t, J=1.4 Hz), 1.30-1.60 (4H, m), 1.76-1.89(2H, m), 3.95 (3H, s), 4.03 (2H, t, J=1.3 Hz), 6.84 (1H, s), 6.98 (2H,d, J=1.4 Hz), 7.99 (2H, d, J=1.4 Hz), 8.01 (2H, d, J=1.7 Hz), 8.13 (2H,d, J=1.7 Hz).

MASS (m/z): 369 (M⁺+1).

PREPARATION 345

Dimethylformamide (123 l),1-(4-methoxycarbonylphenyl)-3-(4-pentyloxyphenyl)propane-1,3-dione (24.5kg) and ammonium formate (21.0 kg) were charged in 2000-liter reactor atroom temperature and heated, and a reaction was carried out at the innertemperature of 100 to 105° C. for 5 hours. After completion of thereaction, the mixture was cooled down to room temperature, ethyl acetate(613 l) and water (613 l) were added, the mixture was stirred, and anethyl acetate layer was separated, and then washed with 10% sodiumchloride solution (613 l) and with 20% sodium chloride solution (613 l).The ethyl acetate layer was concentrated in vacuo to 125 l and thendiluted with n-heptane (625 l) at the inner temperature of 40 to 45° C.to separate crystals of1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene.The cyrstals were filtered at room temperature and washed with a mixtureof n-heptane (104 l) and ethyl acetate (21 l). The crystals were driedovernight in vacuo and purified by suspending in a 70% aqueous acetone(158 l) to give1-amino-1-(4-methoxycarbonylphenyl)-3-oxo-3-(4-pentyloxyphenyl)-1-propene(14.3 kg).

NMR (CDCl₃, δ): 0.94 (3H, t, J=1.4 Hz), 1.30-1.55 (4H, m), 1.70-1.90(2H, m), 3.96 (3H, s), 4.01 (2H, t, J=1.3 Hz), 6.13 (1H, br s), 6.92(2H, d, J=1.8 Hz), 7.70 (2H, d, J=1.7 Hz), 7.92 (2H, d, J=1.8 Hz), 8.13(2H, d, J=1.7 Hz).

MASS (m/z): 368 (M⁺+1).

The Starting Compounds used and the Object Compounds obtained in thefollowing Examples 1 to 17 are given in the table as below, in which theformulas of the starting compounds are in the upper column and theformulas of the object compounds are in the lower column, respectively.

Example No. Formula  1

 2

3˜13

Example No. R X  3

Na  4

Na  5

Na  6

Na  7

 8

 9

Na 10

Na 11

Na 12

13

Na Example No. Formula 14

15

16

17

EXAMPLE 1

A solution of crude Starting compound (5.6 g) in methanol (168 ml)-water(336 ml) was treated with cobalt chloride hexahydrate (3.08 g) and themixture stirred to give a pink colored solution. Sodium borohydride(2.46 g) was then added portionwise over 1 hour. Additional cobaltchloride (1.54 g) was added followed by sodium borohydride (1.23 g,portionwise). After a total reaction time of 2 hours 50% aqueousacetonitrile (600 ml) was added and insoluble material removed byfiltration. The filtrate was evaporated to remove organic solvent andsufficient 1N-sodium hydroxide was added to the remaining aqueous layerto effect solution. This clear aqueous solution was then purified by ODScolumn chromatography eluting with aqueous acetonitrile. Objectcompounds-containing fractions were pooled, evaporated, and lyophilizedto give Object compound (1.4 g) as an amorphous white powder.

IR (KBr): 1658.5, 1635.3, 1546.6, 1529.3, 1517.7, 1444.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.8 Hz), 1.10 (3H, d, J=6 Hz),1.30-1.60 (8H, m), 1.60-2.50 (15H, m), 3.21 (3H, s), 2.80-5.40 (29H, m),6.74 (1H, d, J=8.2 Hz), 6.80-6.85 (1H, m), 7.07 (1H, br s), 7.14 (2H, d,J=8.9 Hz), 7.40-7.80 (4H, m), 7.97 (2H, d, J=8.8 Hz), 8.09 (4H, ABqlike, br m), 8.20-8.30 (1H, m), 8.80-8.90 (1H, m).

MASS (m/z): 1313.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₇₈N₁₀O₂₁S₂.9H₂O: C, 47.34, H, 6.16, N,9.52. Found: C, 47.42, H, 6.26, N, 9.47.

The following compounds [Examples 2 to 13] were obtained according to asimilar manner to that of Example 1.

EXAMPLE 2

IR (KBr): 1648.8, 1631.5, 1538.9, 1515.8, 1442.5, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.24 (3H, d, J=5.6 Hz),1.40-1.60 (8H, m), 1.60-2.65 (15H, m), 2.80-5.50 (27H, m), 3.21 (3H, s),3.30 (2H, t, J=6.3 Hz), 6.72 (1H, d, J=8.1 Hz), 6.78 (1H, dd, J=1.6 and8.3 Hz), 7.00 (1H, d, J=1.6 Hz), 7.13 (2H, d, J=8.9 Hz), 7.46 (1H, d,J=8.1 Hz), 7.60-7.90 (2H, m), 7.97 (2H, d, J=8.7 Hz), 8.04-8.14 (4H, m),8.24-8.27 (1H, m), 8.70-9.00 (2H, m).

MASS (m/z): 1297.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₇₈N₁₀O₂₀S₂.7.5H₂O: C, 48.56, H, 6.53,N, 9.76. Found: C, 48.56, H, 6.31, N, 9.63.

EXAMPLE 3

IR (KBr): 1633.4, 1517.7, 1444.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.13 (3H, d, J=5.7 Hz),1.20-1.65 (10H, m), 1.65-2.65 (15H, m), 2.70-5.50 (27H, m), 3.21 (3H,s), 4.07 (2H, t, J=6.5 Hz), 6.71 (1H, d, J=8 Hz), 6.75-6.80 (1H, m),6.98 (1H, d, J=1.6 Hz), 7.13 (2H, d, J=8.9 Hz), 7.46 (1H, d, J=8 Hz),7.55-7.85 (2H, m), 7.97 (2H, d, J=8.8 Hz), 8.07 (4H, ABq, J=10.8 Hz),8.09-8.13 (1H, m), 8.79 (1H, d, J=7.9 Hz), 8.55-9.00 (1H, br s).

MASS (m/z): 1311.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₉H₈₀N₁₀O₂₀S₂.10H₂O: C, 47.45, H, 6.75,N, 9.38. Found: C, 47.68, H, 6.27, N, 9.21.

EXAMPLE 4

IR (KBr): 1648.8, 1631.5, 1540.8, 1513.8, 1452.1 cm⁻¹.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.6 Hz), 1.07 (3H, d, J=6 Hz), 1.1-2.7(21H, m), 2.7-5.5 (32H, m), 6.68-6.74 (2H, m), 6.9-6.94 (1H, m), 7.13(2H, d, J=8.9 Hz), 7.2-7.5 (1H, m), 7.5-7.8 (2H, m), 7.97 (2H, d, J=8.8Hz), 8.09 (4H, s), 8.29 (1H, d, J=7.3 Hz), 8.5-8.9 (2H, m).

MASS (m/z): 1283.3 (M⁺−1).

EXAMPLE 5

IR (KBr): 1635.3, 1531.2, 1444.4, 1251.6 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.14 (3H, d, J=6 Hz),1.40-5.30 (41H, m), 3.67-3.70 (2H, m), 4.15-4.23 (2H, m), 6.66 (1H, d,J=8 Hz), 6.64-6.72 (1H, m), 6.96 (1H, br s), 7.09 (2H, d, J=8.9 Hz),7.4-7.8 (4H, m), 7.57 (2H, d, J=6.3 Hz), 7.74 (2H, d, J=8.8 Hz), 8.0-8.3(7H, m), 8.73 (1H, d, J=7.5 Hz).

MASS (m/z): 1304.3 (M⁺).

Elemental Analysis Calcd. for C₅₉H₇₂N₁₀O₂₀S₂.11H₂O: C, 47.13, H, 6.30,N, 9.32. Found: C, 47.22, H, 5.90, N, 8.82.

EXAMPLE 6

IR (KBr): 1635.3, 1531.2, 1508.1, 1444.4, 1251.6 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.14 (3H, d, J=5.4 Hz),1.3-5.3 (44H, m), 3.25 (3H, s), 4.05 (2H, t, J=6 Hz), 6.70 (1H, d, J=8.2Hz), 6.75-6.79 (1H, m), 6.96 (1H, br s), 7.07 (2H, d, J=8.9 Hz), 7.4-7.8(4H, m), 7.73 (2H, d, J=8.8 Hz), 7.87 (2H, d, J=8.5 Hz), 8.08-8.16 (7H,m), 8.7-8.8 (1H, m).

MASS (m/z): 1332.4 (M⁺).

Elemental Analysis Calcd. for C₆₁H₇₆N₁₀O₂₀S₂.11H₂O: C, 47.84, H, 6.45,N, 9.15. Found: C, 48.10, H, 6.00, N, 8.94.

EXAMPLE 7

IR (KBr): 1635.3, 1606.4, 1531.2, 1496.5, 1444.4, 1419.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.11 (3H, d, J=5.7 Hz),1.05-1.04 (5H, m), 1.50-5.30 (52H, complex m), 6.67 (1H, d, J=5.7 Hz),6.73-6.80 (1H, m), 7.01 (1H, d, J=1.6 Hz), 7.08 (2H, d, J=9 Hz), 7.4-7.8(3H, m), 7.85 (2H, d, J=8.7 Hz), 8.07 (4H, ABq, J=9 Hz), 8.31 (1H, d,J=6.9 Hz), 8.71 (1H, s), 8.91 (1H, d, J=7.4 Hz).

MASS (m/z): 1319.4 (M⁺−1).

Elemental Analysis Calcd. for C₆₀H₈₀N₁₂O₁₈S₂.9H₂O: C, 48.57, H, 6.66, N,11.33. Found: C, 48.77, H, 6.54, N, 11.25.

EXAMPLE 8

IR (KBr): 1635.3, 1529.3, 1519.6, 1467.6, 1446.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.91 (3H, t, J=7 Hz), 0.96 (3H, d, J=8.3 Hz), 1.12(3H, d, J=5.6 Hz), 1.2-2.6 (17H, m), 2.6-5.4 (29H, m), 6.71 (1H, d, J=8Hz), 6.77 (1H, br d, J=8 Hz), 6.98 (1H, d, J=1.7 Hz), 7.14 (2H, d, J=8.9Hz), 7.45 (1H, d, J=8.5 Hz), 7.4-7.8 (3H, m), 7.90 (2H, d, J=8.8 Hz),8.05 (4H, s), 8.1-8.3 (1H, s), 8.64 (1H, d, J=6.9 Hz), 8.85 (1H, s).

MASS (m/z): 1278.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₇H₇₃N₁₁O₁₉S₂.9H₂O: C, 47.46, H, 6.36, N,10.68. Found: C, 47.58, H, 6.17, N, 10.62.

EXAMPLE 9

IR (KBr): 3361.3, 2937.1, 1635.3, 1523.5, 1461.8, 1251.6 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.10 (3H, d, J=5.9 Hz),1.2-5.3 (49H, m), 6.67-6.80 (2H, m), 7.01 (1H, d, J=1.6 Hz), 7.15 (2H,d, J=9 Hz), 7.4-7.8 (3H, m), 7.88 (2H, d, J=8.8 Hz), 7.96 (4H, s), 8.35(1H, d, J=8.3 Hz), 8.7-8.8 (2H, m), 8.86 (1H, s).

API-ES MASS (Negative): 1290.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₇₃N₁₁O₁₉S₂.8H₂O: C, 48.29 H 6.26, N,10.53. Found: C, 48.49 H 6.24, N, 10.73.

EXAMPLE 10

IR (KBr): 1637.3, 1523.5, 1459.9, 1238.1 cm⁻¹.

MASS (m/z): 1358.4 (M⁺−1).

EXAMPLE 11

IR (KBr): 3357.5, 1631.5, 1517.7, 1465.6, 1450.2, 1241.9 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.8 Hz), 1.10 (3H, d, J=6 Hz), 1.18(6H, d, J=6 Hz), 1.5-2.7 (11H, m), 2.8-5.4 (33H, m), 6.71 (1H, d, J=8.2Hz), 6.78 (1H, dd, J=8 and 1.6 Hz), 7.01 (1H, d, J=1.6 Hz), 7.12 (2H, d,J=9 Hz), 7.44 (1H, d, J=8.7 Hz), 7.6-7.9 (1H, m), 7.67 (1H, d, J=8 Hz),7.78 (2H, d, J=8.8 Hz), 7.96 (4H, s), 8.35 (1H, d, J=7 Hz), 7.6-8.8 (1H,br s), 8.75 (1H, d, J=7 Hz), 8.81 (1H, s).

API-ES MASS (Negative): 1305.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₇₄N₁₂O₁₉S₂.8H₂O: C, 48.05, H, 6.24, N,11.55. Found: C, 47.99, H, 6.25, N, 11.58.

EXAMPLE 12

IR (KBr): 1631.5, 1510.0, 1446.4, 1234.2 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.8 Hz),1.2-2.65 (15H, m), 2.7-5.3 (41H, m), 3.21 (3H, s), 3.30 (2H, t, J=6.4Hz), 3.85 (2H, t, J=6.5 Hz), 6.70 (1H, d, J=8.2 Hz), 6.74-6.80 (1H, m),6.83 (2H, d, J=9 Hz), 6.94 (2H, d, J=9 Hz), 6.99 (1H, s), 7.01 (2H, d,J=8.8 Hz), 7.44 (1H, d, J=8.6 Hz), 7.6-7.9 (2H, m), 7.80 (2H, d, J=8.7Hz), 8.1-8.3 (2H, m), 8.37 (1H, d, J=7.7 Hz).

MASS (m/z): 1297.5 (M⁺−Na).

Elemental Analysis Calcd. for C₆₀H₈₆N₁₀O₂₀S.7H₂O: C, 50.55, H, 7.07, N,9.83. Found: C, 50.68, H, 7.08, N, 9.82.

EXAMPLE 13

IR (KBr): 1648.8, 1631.5, 1540.8, 1511.9, 1454.1, 1238.1 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.3 (18H, m), 1.5-2.5 (24H, m), 2.61 (4H, br s),2.8-5.4 (27H, m), 6.70 (1H, d, J=8.1 Hz), 6.77 (1H, br d, J=10 Hz), 6.92(2H, d, J=9 Hz), 7.00 (1H, d, J=1.6 Hz), 7.42 (1H, d, J=8.6 Hz), 7.5-7.7(2H, m), 7.76 (2H, d, J=8.6 Hz), 8.30 (1H, d, J=7.1 Hz), 8.44 (1H, d,J=6.9 Hz), 8.46-9.00 (1H, br s).

MASS (m/z): 1241.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₈₆N₁₀O₁₈S.10H₂O: C, 48.94, H, 7.50, N,9.84. Found: C, 49.19, H, 7.33, N, 9.73.

EXAMPLE 14

A solution of Starting compound (150 mg) in N,N-dimethylformamide (1.5ml) was treated with diisopropylethylamine (166.5 mg) and ethylformimidate hydrochloride (64.8 mg) and stirred 2 days at roomtemperature. Additional ethyl formimidate hydrochloride (39 mg) wasadded and stirring continued a further 3 hours 15 minutes. The reactionmixture was diluted with water and purified by ODS columnchromatography, eluting with aqueous acetonitrile. Product-containingfractions were pooled, evaporated, and lyophilized to give Objectcompound as an amorphous white powder.

IR (KBr): 1658.5, 1635.3, 1444.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=6.1 Hz),1.20-1.60 (8H, m), 1.60-2.50 (15H, m), 3.21 (3H, s), 2.80-5.30 (27H, m),6.71 (1H, d, J=8.1 Hz), 6.78 (1H, d, J=6 Hz), 7.00 (1H, br s), 7.14 (2H,d, J=8.9 Hz), 7.40-7.84 (4H, m), 7.84 (1H, s), 7.97 (2H, d, J=8.8 Hz),8.08 (4H, ABq, J=8.9 Hz), 8.30-8.40 (2H, m), 8.90-9.10 (2H, m).

MASS (m/z): 1325.4 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₇₉N₁₁O₁₉S₂.8H₂O: C, 48.29, H, 6.64, N,10.68. Found: C, 48.01, H, 6.34, N, 10.38.

The following compounds [Examples 15 to 17] were obtained according to asimilar manner to that of Example 14.

EXAMPLE 15

IR (KBr): 1658, 1635, 1628, 1444, 1257 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.11 (3H, d, J=6.1 Hz),1.25-1.60 (8H, m), 1.60-2.50 (15H, m), 2.05 (3H, s), 3.21 (3H, s),2.80-5.30 (27H, m), 6.71 (1H, d, J=8.1 Hz), 6.77 (1H, d, J=8 Hz), 7.00(1H, br s), 7.13 (2H, d, J=8.9 Hz), 7.30-7.90 (4H, m), 7.97 (2H, d,J=8.7 Hz), 8.08 (4H, ABq, J=8.8 Hz), 8.50-9.00 (4H, m).

MASS (m/z): 1362.3 (M⁺−Na).

Elemental Analysis Calcd. for C₅₉H₈₁N₁₁O₁₉S₂.9H₂O: C, 48.06, H, 6.77, N,10.45. Found: C, 48.02, H, 6.48, N, 10.11.

EXAMPLE 16

IR (KBr): 1643.1, 1633.4, 1535.1, 1513.8, 1442.5, 1249.6 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.1-1.16 (3H, m), 1.12 (3H, t,J=7 Hz), 1.4-2.6 (12H, m), 2.8-5.2 (34H, m), 6.71 (1H, d, J=8 Hz), 6.78(1H, dd, J=8 and 2 Hz), 7.00 (1H, d, J=2 Hz), 7.08 (2H, d, J=8.8 Hz),7.45 (1H, d, J=8.9 Hz), 7.6-7.8 (2H, m), 7.73 (2H, d, J=8.8 Hz), 7.87(2H, d, J=8.5 Hz), 8.0-8.2 (6H, m), 8.28 (1H, d, J=7 Hz), 8.91 (1H, d,J=7.6 Hz), 8.5-9.05 (1H, br s).

MASS (m/z): 1331.2 (M⁺−1).

Elemental Analysis Calcd. for C₆₁H₇₆N₁₀O₂₀S₂.10H₂O: C, 48.41, H, 6.39,N, 9.25. Found: C, 48.63, H, 6.13, N, 9.13.

EXAMPLE 17

IR (KBr): 1631.5, 1537.0, 1510.0, 1448.3, 1234.2 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.96 (3H, d, J=6.7 Hz), 1.05-1.15 (3H, m), 1.2-3.0(33H, m), 3.15 (3H, s), 3.29 (2H, t, J=6.4 Hz), 3.88 (2H, t, J=6.4 Hz),3.6-4.5 (14H, m), 4.7-4.85 (2H, m), 6.73-7.04 (9H, m), 7.75-7.9 (2H, m).

MASS (m/z): 1311.4 (M⁺−1).

Elemental Analysis Calcd. for C₆₁H₈₈N₁₀O₂₀S.10H₂O: C, 49.05, H, 7.29, N,9.38. Found: C, 48.78, H, 6.83, N, 9.27.

The Starting Compounds (18) to (21) used and the Object Compounds (18)to (21) obtained in the following Examples 18 to 21 are given in thetable as below, in which the formulas of the starting compounds are inthe upper column and the formulas of the object compounds are in thelower column, respectively.

Example No. Formula 18

19

20

21

EXAMPLE 18

A solution of Starting compound (2.0 g) in methanol (100 ml)-water (20ml) was treated with cobalt(II) chloride hexahydrate (1.89 g) and thenstirred to give a pink solution. Sodium borohydride (1.5 g) was thenadded portionwise and then stirred for 1 hour at room temperature. Thereaction mixture was filtered through a bed of celite, washing withmethanol (100 ml)-water (30 ml) solution. The ice-cooled filtrate wasthen treated dropwise with a solution of benzyloxy carbonyl chloride(Z-chloride) (0.34 ml) in tetrahydrofuran (5 ml) and stirred for 1 hourat the same temperature. Ethyl acetate (50 ml) was added followed bywater (200 ml) and after stirring-5 minutes, the separated organic layerwas discarded. The aqueous layer was adjusted to pH 8.8 and evaporatedto remove organic solvent and then purified by ODS columnchromatography, eluting with aqueous acetonitrile (10-30%). Objectcompound containing fractions were pooled, evaporated, and lyophilizedto give Object compound (1.61 g) as an amorphous white powder.

IR (KBr): 1666.2, 1631.5, 1517.7, 1444.4, 1267.0 cm⁻¹.

NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6.7 Hz), 1.00-1.15 (3H, m), 1.33 (9H,s), 1.35-2.10 (6H, m), 2.10-2.50 (4H, m), 2.80-3.30 (4H, m), 3.60-4.55(12H, m), 4.60-4.90 (2H, m), 4.99 (2H, s), 4.50-5.30 (4H, m), 6.60-7.10(4H, m), 7.33 (5H, s), 7.35-7.90 (3H, m), 8.72 (1H, br s).

MASS (m/z): 1123.3 (M⁺−Na).

Elemental Analysis Calcd. for C₄₈H₆₇N₈O₂₁SNa.6H₂O: C, 45.93, H, 6.34, N,8.93. Found: C, 45.68, H, 6.33, N, 8.82.

EXAMPLE 19

A suspension of Starting compound (1.6 g) in dichloromethane (41 ml) wasstirred with cooling at 5° C. and treated with triethylsilane (1.1 ml),followed by trifluoroacetic acid (5.3 ml) dropwise over 30 minutes.After warming to room temperature, the clear solution was stirred for 2hours, then poured into 450 ml of pH 6.86 phosphate buffer and adjustedto pH 8.5 with 4N-sodium hydroxide solution. Organic solvent was removedby evaporation and the remaining aqueous solution purified by ODS columnchromatography, eluting with aqueous acetonitrile (5-20%). Objectcompound-containing fractions were pooled, evaporated, and lyophilizedto give Object compound (1.25 g) as an amorphous white powder.

IR (KBr): 1633.4, 1537.0, 1517.7, 1440.6, 1267.0 cm⁻¹.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.7 Hz), 1.12 (3H, d, J=5.8 Hz), 1.27(2H, d, J=6.6 Hz), 1.28-1.70 (2H, m), 1.75-2.45 (4H, m), 2.65-3.30 (5H,m), 3.50-4.50 (11H, m), 4.60-4.90 (2H, m), 5.00 (2H, s), 5.05-5.40 (5H,m), 6.70 (2H, d, J=8.2 Hz), 6.76 (2H, d, J=8.2 Hz), 6.96 (1H, s),7.00-7.15 (1H, m), 7.34 (5H, s), 7.40-7.95 (3H, m), 8.60-8.90 (1H, m).

MASS (m/z): 1023.3 (M⁺−H).

Elemental Analysis Calcd. for C₄₃H₆₀N₈O₁₉S.6H₂O: C, 45.5H, H, 6.40, N,9.89. Found: C, 45.49, H, 6.24, N, 9.70.

EXAMPLE 20

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.6 Hz), 6.67 (1H, d, J=6.9 Hz),6.73-6.75 (1H, m), 6.96 (1H, br s), 7.07 (2H, d, J=8.8 Hz), 7.32 (5H,s), 7.73 (2H, d, J=8.7 Hz), 7.87 (2H, d, J=8.5 Hz), 8.06-8.14 (6H, m),8.72 (1H, s), 8.80 (1H, d, J=7.1 Hz).

MASS (m/z): 1465.5 (M⁺−Na).

EXAMPLE 21

The Object Compound (21) was used directly in the next reaction withoutpurification.

The Starting compounds (22) to (206) used and the Object Compounds (22)to (206) obtained in the following Example 22 to 206 are given in thetable as below, in which the formulas of the starting compounds are inthe upper column and the formulas of the object compounds are in thelower column, respectively.

Example No. Formula 22

23

24

25

26

27

28

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EXAMPLE 22

A solution of starting compound (22) (670 mg) and 10% palladium oncarbon (50%, including water) (0.8 g) in a mixture of methanol (10 ml)and water (10 ml) was hydrogenated under an atmospheric pressure ofhydrogen with stirring at ambient temperature for 12 hours. The catalystwas filtered off and washed with a mixture of methanol and water (1:1v/v) (50 ml), and the filtrate and washes were combined. To the solutionwas added dropwise allyloxycarbonyl chloride (3.0 ml) adjusting pH to8.5-10.0 with 1N sodium hydroxide with stirring on an ice-bath. Themixture was stirred at the same temperature for 2 hours and concentratedin vacuo. The resulting residue was dissolved in 1N sodium hydroxide (20ml) and allowed to stand at 4° C. overnight. The solution was subjectedto column chromatography on ODS (Daiso-gel, SP-120-40/60-ODS-B(Trademark: prepared by Daiso Co., Ltd.)) (100 ml) eluting with 10%acetonitrile in water. The fractions containing the object compound werecollected and evaporated under reduced pressure to remove acetonitrile.The residue was lyophilized to give object compound (22) (379 mg).

NMR (DMSO-d₆+D₂O, δ): 0.96 (3H, d, J=6.73 Hz), 1.07 (3H, broad s), 1.36(9H, s), 1.40-2.40 (8H, m), 2.70-3.45 (5H, m), 2.01 (3H, d, J=4.26 Hz),3.21 (3H, s), 3.31 (4H, t, J=6.34 Hz), 3.70-4.50 (14H, m), 4.85-4.90(2H, m), 3.60-4.95 (18H, m), 6.69 (1H, d, J=8.25 Hz), 6.75 (1H, d,J=9.54 Hz), 6.98 (1H, s).

ESI MASS (m/z) (Negative): 1135.3 (M⁺+Na).

EXAMPLE 23

To a solution of starting compound (23) (1.0 g) in DMF (10 ml) wereadded 2-(tert-butoxycarbonyloxyimino)-2-phenylacetonitrile (0.30 g) anddiisopropylethylamine (0.27 ml) with stirring at ambient temperature,and the mixture was stirred at the same temperature for 2 hours. To thereaction mixture was added pH 6.86 standard buffer solution (100 ml),and the solution was subjected to column chromatography on ODS(Daiso-gel, SP-120-40/60-ODS-B (Trademark: prepared by Daiso Co., Ltd.))(100 ml) eluting with 20% acetonitrile in water. The fractionscontaining the object compound were collected and evaporated underreduced pressure to remove acetonitrile. The residue was lyophilized togive object compound (23) (302 mg).

IR (KBr): 1668, 1633, 1516, 1441, 1277, 1252 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.97 (3H, d, J=6.64 Hz), 1.07 (3H, d, J=5.96 Hz),1.37 (9H, s), 1.40-2.00 (4H, m), 2.10-2.50 (4H, m), 2.60-3.40 (6H, m),3.60-4.50 (10H, m), 4.65-4.85 (2H, m), 6.71 (1H, d, J=8.14 Hz), 6.78(1H, d, J=8.39 Hz), 6.98 (1H, s).

ESI MASS (m/z) (Negative): 989.3 (M⁺−1).

Elemental Analysis Calcd. for C₄₀H₆₂N₈O₁₉S.5H₂O: C, 44.44, H, 6.71, N,10.36. Found: C, 44.23, H, 6.42, N, 9.82.

EXAMPLE 24

A solution of starting compound (24) (211 mg),1-methylpyrazole-4-carboxaldehyde (21.4 mg), acetic acid (29.2 mg) andsodium cyanoborohydride (13.3 mg) in 1:1 methanol-N,N-dimethylformamide(6 ml) was stirred 2 days at room temperature, then treated with ethylacetate and the precipitate was collected, washed with ethyl acetate anddried. This crude material was dissolved in N,N-dimethylformamide (3ml), then treated with diisopropylethylamine (42 mg) and1,1′-carbonyldiimidazole (34.2 mg). After 2 hours at room temperature,further diisopropylethylamine (42 mg) and 1,1′-carbonyldiimidazole (34.2mg) were added. After 4 hours, the solution was diluted with pH 6.86standard buffer solution and the solution was subjected to ODS columnchromatography eluting with acetonitrile in water mixtures. Fractionscontaining the object compounds were pooled, evaporated and lyophilizedseparately to afford major object compound (24) (60 mg) and minor objectcompound (24) (55 mg) as white amorphous powders.

Major Object Compound (24)

IR (KBr): 2935, 1658.5, 1635, 1444, 1259 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.9-1.05 (6H, m), 1.23-5.00 (43H, m), 3.22 (3H,s), 3.33 (2H, t, J=6.6 Hz), 3.69 (3H, s), 6.76 (1H, d, J=7.7 Hz),6.81-6.86 (1H, m), 7.07 (1H, br s), 7.15 (2H, d, J=9 Hz), 7.43 (1H, s),7.68 (1H, s), 7.94-8.19 (6H, m).

MASS (m/z): 1417.4 (M⁺−Na).

Elemental Analysis Calcd. for C₆₄H₈₁N₁₂O₂₁S₂Na.5H₂O: C, 50.19, H, 5.99,N, 10.97. Found: C, 50.16, H, 6.06, N, 10.82.

Minor Object Compound (24)

IR (KBr): 2935, 2862, 1658.5, 1635, 1529, 1516, 1444, 1412, 1257 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.98 (3H, d, J=6.3 Hz), 1.05 (3H, d, J=5.4 Hz),1.2-4.9 (54H, complex m), 3.21 (3H, s), 3.31 (2H, t, J=6.4 Hz), 6.7-6.75(2H, m), 7.05 (1H, br s), 7.14 (2H, d, J=8.8 Hz), 7.4-8.14 (8H, complexm).

MASS (m/z): 1486.5 (M⁺).

Elemental Analysis Calcd. for C₆₈H₉₀N₁₄O₂₀S₂.6H₂O: C, 51.18, H, 6.44, N,12.29. Found: C, 51.00, H, 6.31, N, 11.81.

EXAMPLE 25

To a solution of starting compound (25) (1.5 g) and(1,3-dioxy-2-oxo-4-cyclopenten-5-yl)methoxycarbonyloxysuccinimide (0.47g) in dimethylformamide (15 ml) was added diisopropylethylamine (0.302ml) and stirred for 5 hours at ambient temperature. The reaction mixturewas pulverized with ethyl acetate. The precipitate was collected byfiltration and dried under reduced pressure. The powder was added to pH6.86 buffer and subjected to column chromatography on ODS (YMC-gelODS-AM-S-50) (Trademark: prepared by Yamamura Chemical Lab.) and elutedwith 5-15% acetonitrile aq. The fractions containing the object compoundwere combined and evaporated under reduced pressure to removeacetonitrile. The residue was lyophilized to give object compound (25)(1.05 g).

IR (KBr): 3350, 1816.6, 1635.3, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.6 Hz), 1.12 (3H, d, J=5.8 Hz),1.2-2.6 (17H, m), 2.13 (3H, s), 2.8-3.4 (7H, m), 3.21 (3H, s), 3.6-5.3(28H, m), 6.72 (1H, d, J=8.2 Hz), 6.78 (1H, d, J=8.2 Hz), 6.88 (1H, s),7.13 (2H, d, J=8.6 Hz), 7.25-7.8 (4H, m), 7.93 (2H, d, J=8.6 Hz), 8.09(4H, s), 8.73 (1H, s), 8.80 (1H, d, J=6.7 Hz).

ESI MASS (m/z): 1453 (M⁺−Na).

Elemental Analysis Calcd. for C₆₄H₈₁N₁₀O₂₅S₂Na.5H₂O: C, 49.04, H, 5.85,N, 8.94. Found: C, 48.98, H, 5.75, N, 9.05.

EXAMPLE 26

To a solution of starting compound (26) (0.2 g) and4-acetyloxymethoxycarbonyloxynitrobenzene (58.9 mg) in dimethylformamide(1.5 ml) was added diisopropylethylamine (0.04 ml) and stirred for 5hours at ambient temperature. The reaction mixture was pulverized withethyl acetate. The precipitate was collected by filtration and driedunder reduced pressure. The powder was added to pH 6.86 buffer andsubjected to column chromatography on ODS (YHC-gel ODS-AM-S-50)(Trademark: prepared by Yamamura Chemical Lab.) and eluted with 5-15%acetonitrile aq. The fractions containing the object compound werecombined and evaporated under reduced pressure to remove acetonitrile.The residue was lyophilized to give object compound (26) (26 mg).

IR (KBr): 3365.2, 1751.0, 1727.9, 1635.3, 1259.3 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.6 Hz), 1.12 (3H, d, J=5.8 Hz),1.2-2.6 (17H, m), 2.04 (3H, s), 2.8-3.4 (7H, m), 3.21 (3H, s), 3.6-5.3(26H, m), 5.61 (2H, s), 6.70 (1H, d, J=8.2 Hz), 6.77 (1H, d, J=8.2 Hz),6.96 (1H, s), 7.13 (2H, d, J=8.6 Hz), 7.25-7.8 (4H, m), 7.93 (2H, d,J=8.6 Hz), 8.09 (4H, s), 8.73 (1H, s), 8.80 (1H, d, J=6.7 Hz).

ESI MASS (m/z): 1413 (M⁺−Na).

EXAMPLE 27

A solution of 4-piperidone hydrochloride hydrate (28.4 mg) and succinicanhydride (18.5 mg) in DMF (2 ml) was treated with diisopropylethylamine(23.9 mg) and aged for 3 hours at room temperature. To the resultingsolution was added methanol (3 ml), DMF (1 ml), and after 30 minutes,acetic acid (27.7 mg), starting compound (31) (200 mg), and finally,sodium cyanoborohydride (12.6 mg). After 3 days at room temperature,ethyl acetate was added and the precipitate was collected, washed withethyl acetate and dried. This solid was purified by ODS columnchromatography (acetonitrile-water) to give object compound (27) (164mg) as a white amorphous powder.

NMR (DMSO-d₆+D₂O, δ): 0.96 (3H, d, J=6.6 Hz), 1.12 (3H, d, J=5.6 Hz),1.2-4.9 (54H, complex m), 3.21 (3H, s), 3.31 (2H, t, J=6.4 Hz), 6.7-6.8(2H, m), 6.99 (1H, br s), 7.13 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.9Hz), 8.08 (4H, ABq, J=8.6 Hz, separation of inner lines=6.6 Hz).

MASS (m/z): 1528.3 (M⁺+Na).

Elemental Analysis Calcd. for C₆₇H₉₀N₁₁O₂₃S₂Na.8H₂O: C, 48.81, H, 6.48,N, 9.34. Found: C, 48.84, H, 6.46, N, 9.29.

EXAMPLE 28

To a solution of the starting compound (28) (200 mg) and molecularsieves (4A) (200 mg) in N,N-dimethylformamide (4 ml) was added methyliodide (1 ml), and stirred for 4 days at ambient temperature. Thereaction mixture was filtrated, and the filtrate was diluted in water,and subjected to column chromatography on ODS (YMC-gel-ODS-AM-S-50(Trademark: prepared by Yamamura Chemical Lab.)) eluting with 20%acetonitrile aqueous solution. The fractions containing the objectcompound were combined and evaporated under reduced pressure to removeacetonitrile. The residue was lyophilized to give the object compound(28) (46 mg).

IR (KBr): 3355, 2935, 1664, 1627, 1446, 1405, 1375, 1257, 1178, 1083,1047 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.8 Hz), 1.03 (3H, d, J=6.2 Hz),1.2-1.6 (8H, m), 1.6-2.6 (15H, m), 2.6-3.8 (6H, m), 3.09 (9H, s), 3.21(3H, s), 3.30 (4H, t, J=6.4 Hz), 3.8-4.2 (7H, m), 4.2-4.6 (4H, m),4.6-5.0 (2H, m), 5.28 (2H, m), 5.75 (1H, m), 6.69 (1H, d, J=8.2 Hz),6.80 (1H, d, J=8.2 Hz), 6.92 (1H, s), 7.14 (2H, d, J=8.8 Hz), 7.35 (1H,d, J=7.4 Hz), 7.5 (1H, m), 7.86 (1H, m), 7.97 (2H, d, J=8.8 Hz), 8.09(4H, s), 8.32 (1H, s), 8.76 (1H, d, J=6.8 Hz), 8.95 (1H, s).

MASS (m/z): 1363.4 (M⁺+Na).

EXAMPLE 29

To a solution of starting compound (29) (0.2 g) and ethyl bromoacetate(0.02 ml) in dimethylformamlide (2 ml) was bis added potassium carbonate(30.8 mg) and stirred for 24 hours at ambient temperature. The reactionmixture was pulverized with ethyl acetate. The precipitate was collectedby filtration and dried under reduced pressure. The powder was added to1N NaOH aq. (5 ml) and stirred for 1 hour at ambient temperature. Thereaction mixture was adjusted to pH 7 and subjected to columnchromatography on ODS (YMC-gel ODS-AM-S-50) (Trademark: prepared byYamamura Chemical Lab.) and eluted with 30% acetonitrile aq. Thefractions containing the object compound were combined and evaporatedunder reduced pressure to remove acetonitrile. The residue waslyophilized to give object compound (29) (76 mg).

IR (KBr): 3353.6, 1631.5, 1444.4, 1257.4 cm⁻¹.

ESI-MASS (m/z): 1355 (M⁺−1).

EXAMPLE 30

To a solution of starting compound (30) (0.1 g) and ethyl bromoacetate(0.02 ml) in dimethylformamide (1 ml) was added diisopropylethylamine(0.08 ml) and stirred for 24 hours at ambient temperature. The reactionmixture was pulverized with ethyl acetate. The precipitate was collectedby filtration and dried under reduced pressure. The powder was added to1N NaOH aq. (5 ml) and stirred for 1 hour at ambient temperature. Thereaction mixture was adjusted to pH 7 and subjected to columnchromatography on ODS (YMC-gel ODS-AM-S-50) (Trademark: prepared byYamamura Chemical Lab.) and eluted with 30% acetonitrile aq. Thefractions containing the object compound were combined and evaporatedunder reduced pressure to remove acetonitrile. The residue waslyophilized to give object compound (30) (48 mg).

IR (KBr): 3357.5, 1633.4, 1444.4, 1257.4 cm⁻¹.

ESI-MASS (m/z): 1435 (M⁺+Na).

EXAMPLE 31

A mixture of4-[5-[4-[7-(cis-2,6-dimethylmorpholin-4-yl)heptyloxy]phenyl]isoxazol-3-yl]benzoicacid (100 mg), 1-hydroxybenzotriazole (41 mg) and1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (46.7 mg)in N,N-dimethylformamide (2 ml) was stirred for 30 minutes at ambienttemperature. To the reaction mixture was added N,N-diisopropylethylamine(53.1 μl) and stirred for 40 minutes, then starting compound (31) (246.6mg) was added and the mixture was stirred for 4 hours. To the reactionmixture was added ethyl acetate (50 ml). The resulting precipitate wascollected by filtration and washed with diisopropyl ether to give acrude light-brown powder (400.3 mg). The crude powder was purified bycolumn chromatography on ODS (YMC-gel ODS-AM-S-50 (Trademark: preparedby YMC CO., Ltd.)) (35% acetonitrile aqueous solution). The fractionscontaining the object compound were combined, and evaporated underreduced pressure to remove acetonitrile. The residue was lyophilized togive object compound (31).

IR (KBr): 3372.9, 1666.2, 1648.8, 1631.5, 1538.9, 1508.9, 1452.1,1436.7, 1257.4 cm⁻¹.

MASS (m/z): 1447.6 (M⁻−1).

Elemental Analysis Calcd. for C₆₈H₉₂N₁₀O₂₃S.7H₂O: C, 51.83, H, 6.78, N,8.89. Found: C, 52.10, H, 6.67, N, 8.91.

EXAMPLE 32

To a solution of starting compound (32) (0.1 g) and1-ethoxy-1-imino-3-methoxypropane (38.7 mg) in dimethylformamide (1 ml)was added diisopropylethylamine (0.067 ml) and stirred for 20 hours atambient temperature. The reaction mixture was pulverized with ethylacetate. The precipitate was collected by filtration and dried underreduced pressure. The powder was added to pH 6.86 buffer and subjectedto column chromatography on ODS (YMC-gel ODS-AM-S-50) (Trademark:prepared by Yamamura Chemical Lab.) and eluted with 5-50% acetonitrileaq. The fractions containing the object compound were combined andevaporated under reduced pressure to remove acetonitrile. The residuewas lyophilized to give object compound (32) (42 mg).

IR (KBr): 3353.6, 1635.3, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.6 Hz), 1.13 (3H, d, J=5.8 Hz),1.2-2.6 (19H, m), 2.8-3.4 (9H, m), 3.21 (3H, s), 3.6-5.3 (26H, m), 6.71(1H, d, J=8.2 Hz), 6.77 (1H, d, J=8.2 Hz), 7.00 (1H, s), 7.13 (2H, d,J=8.6 Hz), 7.25-7.8 (3H, m), 7.96 (2H, d, J=8.6 Hz), 8.05 (2H, d, J=8.9Hz), 8.11 (2H, d, J=8.9 Hz), 8.70 (1H, s), 8.85 (1H, d, J=6.7 Hz).

MASS (m/z): 1383 (M⁺−1).

Elemental Analysis Calcd. for C₆₂H₈₅N₁₁O₂₁S₂.8H₂O: C, 48.71, H, 6.66, N,10.08. Found: C, 48.50, H, 6.50, N, 9.96.

EXAMPLE 33

To a solution of starting compound (33) (0.1 g) and2-carbamoyl-1-ethoxy-1-iminopropane (38.5 mg) in dimethylformamide (1ml) was added diisopropylethylamine (0.067 ml) and stirred for 20 hoursat ambient temperature. The reaction mixture was pulverized with ethylacetate. The precipitate was collected by filtration and dried underreduced pressure. The powder was added to pH 6.86 buffer and subjectedto column chromatography on ODS (YMC-gel ODS-AM-S-50) (Trademark:prepared by Yamamura Chemical Lab.) and eluted with 5-50% acetonitrileaq. The fractions containing the object compound were combined andevaporated under reduced pressure to remove acetonitrile. The residuewas lyophilized to give object compound (33) (48 mg).

IR (KBr): 1658.5, 1635.3, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.6 Hz), 1.13 (3H, d, J=5.8 Hz),1.2-2.6 (17H, m), 2.8-3.4 (7H, m), 3.21 (3H, s), 3.6-5.3 (28H, m), 6.71(1H, d, J=8.2 Hz), 6.77 (1H, d, J=8.2 Hz), 7.00 (1H, s), 7.13 (2H, d,J=8.6 Hz), 7.32 (1H, s), 7.25-7.8 (4H, m), 7.96 (2H, d, J=8.6 Hz), 8.05(2H, d, J=8.9 Hz), 8.11 (2H, d, J=8.9 Hz), 8.70 (1H, s), 8.85 (1H, d,J=6.7 Hz).

ESI-MASS (m/z): 1382 (M⁺−1).

Elemental Analysis Calcd. for C₆₁H₈₂N₁₂O₂₁S₂.7H₂O: C, 48.53, H, 6.41, N,11.13. Found: C, 48.50, H, 6.39, N, 10.92.

EXAMPLE 34

A mixture of starting compound (34) (50 mg), N,N-diisopropylethylamine(6.70 μl) and zeolite synthetic A-4 powder (50 mg) inN,N-dimethylformamide (0.5 ml) was stirred for 30 minutes at ambienttemperature. To the mixture was added acetic anhydride (3.63 μl) andstirred for 2 hours. The zeolite synthetic A-4 powder was filtered off,and to the filtrate was added ethyl acetate (100 ml). The resultingprecipitate was collected by filtration and washed with diisopropylether to give a crude white powder (48.7 mg). The crude powder waspurified by column chromatography on ODS (YMC-gel ODS-AM-S-50(Trademark; prepared by YMC Co., Ltd.)) (25% acetonitrile aqueoussolution). The fractions containing the object compound were combined,and evaporated under reduced pressure to remove acetonitrile. Theresidue was lyophilized to give object compound (34) (31.5 mg).

IR (KBr): 3353.6, 1658.5, 1635.3, 1546.6, 1531.2, 1517.7, 1444.4, 1259.3cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.14 (3H, d, J=5.9 Hz),1.2-5.5 (55H, m), 6.71 (1H, d, J=8.1 Hz), 6.7-6.9 (1H, m), 6.96 (1H, d,J=1.6 Hz), 7.13 (2H, d, J=8.9 Hz), 7.3-7.8 (4H, m), 7.97 (2H, d, J=8.8Hz), 7.9-9.0 (7H, m).

MASS (m/z): 1339.3 (M⁻−Na).

Elemental Analysis Calcd. for C₆₀H₇₉N₁₀NaO₂₁S₃.10H₂O: C, 46.69, H, 6.46,N, 9.07. Found: C, 46.46, H, 6.11, N, 8.95.

EXAMPLE 35

A solution of starting compound (35) (500 mg) in water (20 ml) and1N-sodium hydroxide (1.15 μl) was treated dropwise with a solution ofallyloxycarbonyl chloride (49 μl) in tetrahydrofuran (1 ml). After 1hour, the solution was diluted with water and purified by ODS columnchromatography eluting with acetonitrile-water mixtures.Product-containing fractions were pooled, evaporated to remove organicsolvent and lyophilized to give object compound (35) (350 mg) as a whiteamorphous powder.

IR (KBr): 2935, 1664, 1633, 1610, 1527, 1442.5, 1412, 1383, 1348, 1257,1178, 1113, 1088, 1045 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.97 (3H, d, J=6.7 Hz), 1.11 (3H, d, J=5.8 Hz),1.2-5.1 (53H, complex m), 3.21 (3H, s), 3.31 (2H, t, J=6.4 Hz),5.12-5.29 (2H, m), 5.8-6.0 (1H, m), 6.70-6.80 (2H, m), 6.99 (1H, br s),7.14 (2H, d, J=8.8 Hz), 7.98 (2H, d, J=8.8 Hz), 8.09 (4H, s).

MASS (M/z): 1381.3 (M⁺−Na).

Elemental Analysis Calcd. for C₆₂H₈₁N₁₀O₂₂S₂Na.5H₂O: C, 49.79, H, 6.13,N, 9.37. Found: C, 49.79, H, 6.07, N, 9.30.

EXAMPLE 36

To a solution of starting compound (36) (100 mg) inN,N-dimethylformamide (1 ml) was added sulfur trioxide pyridine complex(61.2 mg) and stirred for 2 days at ambient temperature. To the reactionmixture was added ethyl acetate (30 ml), and the resulting precipitatewas collected by filtration and washed with diisopropyl ether to give acrude white powder. The crude powder was purified by columnchromatography on ODS (YMC-gel ODS-AM-S-50 (Trademark: prepared by YMCCo., Ltd.)) (20% acetonitrile aqueous solution). The fractionscontaining the object compound were combined, and evaporated underreduced pressure to remove acetonitrile. The residue was lyophilized togive object compound (36) (12.7 mg).

IR (KBr): 3446.2, 1648.8, 1633.4, 1540.8, 1515.8, 1450.2, 1442.5, 1257.4cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.5 Hz), 1.0-5.4 (56H, m), 6.6-6.8 (2H,m), 6.9-7.1 (1H, m), 7.13 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz),8.08 (4H, s), 7.3-9.0 (7H, m).

MASS (m/z): 1399.3 (M⁻−1).

EXAMPLE 37

A mixture of starting compound (37) (100 mg), N,N-diisopropylethylamine(14.7 μl), zeolite synthetic A-4 powder (400 mg) andN,N-dimethylformamide dimethyl acetal (15.3 μl) in N,N-dimethylformamide(1 ml) was stirred for 40 minutes at ambient temperature. To thereaction mixture was added N,N-diisopropylethylamine (1.5 μl) andN,N-dimethylformamide dimethyl acetal (1.5 μl), the mixture was stirredfor 1 hour at ambient temperature, and ethyl acetate (50 ml) was added,and the resulting precipitate was collected by filtration and washedwith diisopropyl ether to give a crude white powder (72.2 mg). The crudepowder was purified by column chromatography on ODS (YMC-gel ODS-AM-S-50(Trademark: prepared by YMC Co., Ltd.)) (40% acetonitrile aqueoussolution). The fractions containing the object compound were combined,and evaporated under reduced pressure to remove acetonitrile. Theresidue was lyophilized to give object compound (37) (27.9 mg).

IR (KBr): 3359.4, 1710.6, 1648.8, 1631.5, 1538.9, 1513.8, 1442.5, 1257.4cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.0-5.4 (62H, m), 6.6-6.9 (2H,m), 6.99 (1H, s), 7.14 (2H, d, J=8.8 Hz), 7.3-7.9 (3H, m), 7.97 (2H, d,J=8.8 Hz), 8.0-8.2 (4H, m), 8.3-9.2 (4H, m).

MASS (m/z): 1352.5 (M⁻−1).

Elemental Analysis Calcd. for C₆₁H₈ ₃N₁₁O₂₀S₂.6H₂O: C, 49.02, H, 6.41,N, 10.31. Found: C, 49.20, H, 6.35, N, 10.27.

EXAMPLE 38

To a solution of the starting compound (38) (100 mg) inN,N-dimethylformamide (1 ml) was added S,S′-dimethylN-cyanodithioiminocarbonate (113 mg) and diisopropyl ethyl amine (0.2ml), and stirred for 2 hours at ambient temperature. The reactionmixture was pulverized with ethyl acetate and washed by diisopropylether. The precipitate was filtered and dried to give the objectcompound (38) (111 mg).

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.0-1.6 (14H, m), 1.6-3.9(25H, m), 3.21 (3H, s), 3.9-4.3 (7H, m), 4.43 (2H, m), 4.5-4.7 (2H, m),4.88 (2H, d, J=5.7 Hz), 5.0-5.3 (4H, m), 6.71 (1H, d, J=8.2 Hz), 6.78(1H, d, J=8.2 Hz), 6.97 (1H, s), 7.13 (2H, d, J=8.8 Hz), 7.50 (1H, d,J=8.5 Hz), 7.63 (1H, m), 7.7 (1H, m), 7.97 (2H, d, J=8.8 Hz), 8.09 (4H,s), 8.12 (1H, m), 8.71 (1H, s), 8.78 (1H, d, J=6.4 Hz).

MASS (m/z): 1395.3 (M⁺−1).

EXAMPLE 39

To a solution of the starting compound (39) (96 mg) in water (1 ml) wasadded a solution of ammonia in methanol (1 ml), and stirred for 2 daysat ambient temperature. The reaction mixture was diluted in water, andsubjected to column chromatography on ODS (YMC-gel ODS-AM-S-50(Trademark: prepared by Yamamura Chemical Lab.)) eluting with 20%acetonitrile aqueous solution. The fractions containing the objectcompound were combined, and evaporated under reduced pressure to removeacetonitrile. The residue was lyophilized to give the object compound(39) (39 mg).

IR (KBr): 3351, 2935, 1635, 1567, 1533, 1517, 1444, 1415, 1257, 1178,1087, 1047 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.13 (3H, d, J=5.7 Hz),1.2-1.6 (11H, m), 1.6-2.6 (10H, m), 2.90 (1H, m), 3.20 (1H, m), 3.21(3H, s), 3.30 (4H, t, J=6.4 Hz), 3.3-4.6 (14H, m), 4.6-4.8 (2H, m), 4.87(1H, d, J=5.7 Hz), 5.06 (1H, d, J=7.2 Hz), 5.2 (4H, m), 6.71 (1H, d,J=8.2 Hz), 6.78 (1H, d, J=8.2 Hz), 6.7 (3H, m), 6.97 (1H, s), 7.13 (2H,d, J=8.8 Hz), 7.46 (1H, d, J=8.8 Hz), 7.65 (2H, m), 7.97 (2H, d, J=8.8Hz), 8.09 (4H, s), 8.13 (1H, m), 8.71 (1H, s), 8.84 (1H, d, J=7.7 Hz).

MASS (m/z): 1364.4 (M⁺−Na).

Elemental Analysis Calcd. for C₆₀H₇₈N₁₃NaO₂₀S₂.8H₂O: C, 47.02, H, 6.18,N, 11.88. Found: C, 47.15, H, 5.89, N, 11.82.

EXAMPLE 40

To a solution of the starting compound (40) (100 mg) in acetonitrile (1ml) and water (1 ml) was added formaline (35% aqueous) (67 μl), andstirred for 30 minutes at ambient temperature. To a solution of thereaction mixture was added sodium cyanoborohydride (48 mg) and stirredfor 5 hours. The reaction mixture was diluted in water, and subjected tocolumn chromatography on ODS (YMC-gel ODS-AM-S-50 (Trademark: preparedby Yamamura Chemical Lab.)) eluting with 20% acetonitrile aqueoussolution. The fractions containing the object compound were combined,and evaporated under reduced pressure to remove acetonitrile. Theresidue was lyophilized to give the object compound (40) (27 mg).

IR (KBr): 3355, 2937, 1658, 1633, 1533, 1517, 1444, 1257, 1178, 1087,1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.3-2.6 (30H, m), 2.6-3.0 (4H, m), 3.21 (3H, s), 3.0-4.1 (11H, m), 4.22(2H, m), 4.4 (4H, m), 4.80 (3H, m), 4.9 (2H, m), 5.17 (2H, m), 5.24 (1H,d, J=5.7 Hz), 6.69 (1H, d, J=8.2 Hz), 6.76 (1H, d, J=8.2 Hz), 6.99 (1H,s), 7.05 (1H, s), 7.14 (2H, d, J=8.8 Hz), 7.41 (2H, d, J=9.1 Hz), 7.85(1H, m), 7.97 (2H, d, J=8.8 Hz), 8.10 (4H, s), 8.70 (1H, m), 8.72 (1H,s), 8.87 (1H, m).

MASS (m/z): 1365.4 (M⁺−1).

Elemental Analysis Calcd. for C₆₃H₈₆N₁₀O₂₀S₂.8H₂O: C, 50.06, H, 6.80, N,9.27. Found: C, 49.95, H, 6.38, N, 9.21.

EXAMPLE 41

To a solution of the starting compound (41) (100 mg) and potassiumcarbonate (53 mg) in N,N-dimethylformamide (1 ml) was added1,5-dibromopentane (13 μl), and stirred for 3 days at ambienttemperature. The reaction mixture was filtrated, and the filtrate wasdiluted in water, and subjected to column chromatography on ODS (YMC-gelODS-AM-S-50 (Trademark: prepared by Yamamura Chemical Lab.)) elutingwith 20% acetonitrile aqueous solution. The fractions containing theobject compound were combined, and evaporated under reduced pressure toremove acetonitrile. The residue was lyophilized to give the objectcompound (41) (38 mg).

IR (KBr): 3353, 2935, 1658, 1635, 1546, 1529, 1517, 1444, 1257, 1083,1047 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.7 Hz),1.3-1.6 (8H, m), 1.6-2.4 (15H, m), 2.4-3.0 (6H, m), 3.21 (3H, s),3.0-4.2 (1H, m), 4.23 (2H, m), 4.43 (4H, m), 4.80 (3H, m), 4.95 (2H, d,J=6.2 Hz), 5.1-5.3 (3H, m), 6.70 (1H, d, J=8.2 Hz), 6.77 (1H, d, J=8.2Hz), 6.99 (1H, s), 7.14 (2H, d, J=8.8 Hz), 7.43 (2H, m), 7.83 (1H, d,J=7.2 Hz), 7.97 (2H, d, J=8.8 Hz), 8.10 (4H, s), 8.60 (1H, m), 8.71 (1H,s), 8.87 (1H, d, J=7.2 Hz).

MASS (m/z): 1325.4 (M⁺−1).

Elemental Analysis Calcd. for C₆₀H₉₂N₁₀O₂₀S₂.8H₂O: C, 48.97, H, 6.71, N,9.52. Found: C, 48.97, H, 6.32, N, 9.63.

EXAMPLE 42

To a solution of the starting compound (42) (200 mg) and molecularsieves (4A) (200 mg) in N,N-dimethylformamide (4 ml) was added cyanogenbromide (80 mg), and stirred for 5 hours at ambient temperature. Thereaction mixture was filtrated, and the filtrate was diluted in water,and subjected to column chromatography on ODS (YMC-gel-ODS-AM-S-50(Trademark: prepared by Yamamura Chemical Lab.)) eluting with 20%acetonitrile aqueous solution. The fractions containing the objectcompound were combined, and evaporated under reduced pressure to removeacetonitrile. The residue was lyophilized to give the object compound(42) (3.8 mg).

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.13 (3H, d, J=5.7 Hz),1.2-1.6 (8H, m), 1.6-4.5 (30H, m), 2.79 (3H, s), 3.21 (3H, s), 4.7 (2H,m), 4.85 (2H, d, J=6.0 Hz), 5.07 (2H, m), 5.2 (3H, m), 6.69 (2H, m),6.95 (1H, s), 7.14 (2H, d, J=8.8 Hz), 7.46 (1H, m), 7.64 (2H, m), 7.97(2H, d, J=8.8 Hz), 8.09 (4H, s), 8.07 (1H, d, J=7.8 Hz), 8.57 (1H, d,J=7.8 Hz), 8.27 (1H, m), 8.68 (1H, m), 8.72 (1H, s).

MASS (m/z): 1336.3 (M⁺−1).

EXAMPLE 43

A solution of starting compound (43) (100 mg) in N,N-dimethylformamide(2 ml) was treated with 1,1′-carbonyldiimidazole (16.2 mg) anddiisopropylethylamine (10.9 mg). After 20 hours, a further 3.7 mg of1,1-carbonyldiimidazole was added. After a further 1 hour, the mixturewas diluted with water and purified by ODS column chromatography elutingwith acetonitrile-water mixtures and product-containing fractionslyophilized to afford 80.8 mg of object compound (43) as a whiteamorphous powder.

IR (KBr): 2935, 2864, 1658.5, 1637, 1529, 1518, 1444, 1257 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.93-1.07 (6H, m), 1.20-4.5 (37H, m), 3.21 (3H,s), 3.31 (2H, t, J=6.4 Hz), 4.07 (2H, t, J=6.3 Hz), 4.81 (1H, m), 4.99(1H, d, J=4 Hz), 6.71 (1H, d, J=8.2 Hz), 6.78-6.83 (1H, m), 6.98 (1H, d,J=1.7 Hz), 7.13 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.9 Hz), 8.02-8.13(4H, m).

MASS (m/z): 1323.2 (M⁺−Na).

Elemental Analysis Calcd. for C₅₉H₇₅N₁₀O₂₁S₂N₉.6H₂O: C, 48.39, H, 6.06,N, 9.56. Found: C, 48.37, H, 6.00, N, 9.61.

The following compound was obtained according to a similar manner tothat of Example 43.

EXAMPLE 44

IR (KBr): 3352, 2935, 2864,1635, 1547, 1516, 1444, 1255, 1174, 1045cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.95 (3H, d, J=6.9 Hz), 1.03 (3H, d, J=5.9 Hz),1.20-5.12 (39H, m), 3.21 (3H, s), 3.31 (2H, t, J=6.4 Hz), 4.07 (2H, t,J=6.1 Hz), 6.72 (1H, d, J=8.2 Hz), 6.82 (1H, dd, J=8.2, 1.7 Hz), 6.99(1H, d, J=1.7 Hz), 7.13 (2H, d, J=8.9 Hz), 7.98 (2H, d, J=8.9 Hz), 8.08(4H, m).

MASS (m/z): 1339.2 (M⁺−Na).

Elemental Analysis Calcd. for C₅₉H₇₅N₁₀O₂₀S₃Na.6H₂O: C, 48.16, H, 5.96,N, 9.52. Found: C, 48.01, H, 5.74, N, 9.43.

EXAMPLE 45

A mixture of starting compound (45) (220 mg) and 1N sodium hydroxideaqueous solution (30 ml) was stirred for 1 hour at ambient temperature.The reaction mixture was adjusted to pH 9 with 1N hydrochloric acid, andpurified by column chromatography on ODS (YMC-gel ODS-AM-S-50(Trademark: prepared by YMC Co., Ltd.)) (20% acetonitrile aqueoussolution). The fractions containing the object compound were combined,and evaporated under reduced pressure to remove acetonitrile. Theresidue was lyophilized to give object compound (45).

IR (KBr): 3382.5, 1658.5, 1635.3, 1444.4, 1257.4, 1087.7, 1045.2 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.9 Hz), 1.11 (3H, d, J=5.0 Hz),1.2-5.4 (64H, m), 6.68 (1H, d, J=8.1 Hz), 6.78 (1H, d, J=8.0 Hz), 6.92(1H, d, J=1.8 Hz), 7.13 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.8 Hz), 8.07(4H, s), 7.3-9.0 (6H, m).

MASS (m/z): 1411.4 (M⁻−Na).

The following compounds were obtained according to a similar manner tothat of Example 45.

EXAMPLE 46

Major Object Compound (46)

IR (KBr): 3353.6, 1658.5, 1635.3, 1546.6, 1529.3, 1517.7, 1444.4, 1257.4cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.3 Hz),1.2-5.4 (70H, m), 6.68 (1H, d, J=8.2 Hz), 6.76 (1H, d, J=9.7 Hz), 6.92(1H, s), 7.13 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.7 Hz), 8.04 (2H, d,J=9.3 Hz), 8.10 (2H, d, J=9.0 Hz), 7.3-9.0 (6H, m).

MASS (m/z): 1453.4 (M⁻−Na).

Elemental Analysis calcd. for C₆₇H₉₃N₁₀NaO₂₂S₂.9H₂O: C, 49.08, H, 6.82,N, 8.54. Found: C, 49.20, H, 6.72, N, 8.56.

Minor Object Compound (46)

IR (KBr): 3353.6, 1658.5, 1635.3, 1567.8, 1550.5, 1533.1, 1517.7,1444.4, 1407.8, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.6 Hz), 1.1-5.4 (88H, m), 6.70 (1H, d,J=8.2 Hz), 6.78 (1H, d, J=9.8 Hz), 6.90 (1H, s), 7.13 (2H, d, J=8.9 Hz),7.97 (2H, d, J=8.8 Hz), 8.07 (4H, s), 7.3-9.0 (6H, m).

MASS (m/z): 1631.4 (M⁻−Na).

Elemental Analysis Calcd. for C₇₆H₁₀₈N₁₀Na₂O₂₄S₂.11H₂O: C, 49.24, H,7.07, N, 7.55. Found: C, 49.22, H, 6.93, N, 7.57.

EXAMPLE 47

deleted

deleted

EXAMPLE 48

A mixture of starting compound (48) (100 mg), N,N-diisopropylethylamine(13.4 μl) and zeolite synthetic A-4 powder (100 mg) inN,N-dimethylformamide (1 ml) was stirred for 30 minutes at ambienttemperature. The mixture was cooled to 0° C. and treated withmethanesulfonyl chloride (6 μl) and stirred for 30 minutes at ambienttemperature. The mixture was then treated with further methanesulfonylchloride (6 μl) and stirred for 30 minutes at ambient temperature. Tothe mixture was added N,N-diisopropylethylamine (13.4 μl) and stirredfor 15 minutes at ambient temperature. The mixture was treated withmethanesulfonyl chloride (6 μl) and stirred for 30 minutes at ambienttemperature. To the mixture was added N,N-diisopropylethylamine (13.4μl) and stirred for 15 minutes at ambient temperature. The zeolitesynthetic A-4 powder was filtered off, and to the filtrate was addedethyl acetate (100 ml). The resulting precipitate was collected byfiltration and washed with diisopropyl ether to give a crude powder. Thecrude powder was purified by column chromatography on ODS (YMC-gelODS-AM-S-50 (Trademark: prepared by YMC Co., Ltd.)) (25% acetonitrileaqueous solution). The fractions containing the object compound werecombined, and evaporated under reduced pressure to remove acetonitrile.The residue was lyophilized to give object compound (48) (30.0 mg).

IR (KBr): 3430.7, 1658.5, 1635.3, 1444.4, 1259.3 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.14 (3H, d, J=5.9 Hz),1.2-5.5 (55H, m), 6.6-6.9 (3H, m), 6.97 (1H, d, J=1.6 Hz), 7.13 (2H, d,J=8.9 Hz), 7.3-7.8 (3H, m), 7.97 (2H, d, J=8.8 Hz), 8.09 (4H, s),8.0-9.0 (3H, m).

MASS (m/z): 1375.3 (M⁻−Na).

Elemental Analysis Calcd. for C₅₉H₇₉N₁₀NaO₂₂S₃.7H₂O: C, 46.45, H, 6.14,N, 9.18. Found: C, 46.26, H, 6.11, N, 9.01.

The following compounds [Examples 49 to 52] were obtained according to asimilar manner to that of Example 48.

EXAMPLE 49

IR (KBr): 3380.6, 1666.2, 1648.8, 1631.5, 1538.9, 1513.8, 1450.2,1450.2, 1261.2 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.6 Hz), 1.16 (3H, d, J=5.9 Hz),1.2-5.5 (60H, m), 6.4-6.6 (1H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H, d,J=9.8 Hz), 6.96 (1H, s), 7.13 (2H, d, J=8.8 Hz), 7.3-8.2 (4H, m), 7.93(2H, d, J=8.6 Hz), 8.05 (2H, d, J=9.0 Hz), 8.11 (2H, d, J=8.9 Hz),8.5-9.0 (2H, m).

MASS (m/z): 1410.4 (M⁻−Na).

Elemental Analysis Calcd. for C₆₃H₈₄N₁₁NaO₂₂S₂.8H₂O: C, 47.93, H, 6.38,N, 9.76. Found: C, 48.05, H, 6.25, N, 9.56.

EXAMPLE 50

IR (KBr): 3363.2, 1666.2, 1648.8, 1631.5, 1540.8, 1513.8, 1450.2,1442.5, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.6 Hz), 1.16 (3H, d, J=5.9 Hz),1.2-5.5 (58H, m), 6.1-6.3 (1H, m), 6.71 (1H, d, J=18.1 Hz), 6.78 (1H, d,J=10.0 Hz), 6.96 (1H, s), 7.13 (2H, d, J=8.8 Hz), 7.4-7.9 (4H, m), 7.97(2H, d, J=8.7 Hz), 8.06 (2H, d, J=10.4 Hz), 8.11 (2H, d, J=9.0 Hz),8.6-8.8 (2H, m).

MASS (m/z): 1368.4 (M⁻−Na).

Elemental Analysis Calcd. for C₆₁H₈₂N₁₁NaO₂₁S₂.9H₂O: C, 47.13, H, 6.48,N, 9.91. Found: C, 47.36, H, 6.24, N, 9.86.

EXAMPLE 51

IR (KBr): 3359.4, 1666.2, 1648.8, 1631.5, 1540.8, 1513.8, 1450.2,1442.5, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.1 (9H, m), 1.17 (3H, d, J=6.0 Hz), 1.2-5.5 (56H,m), 6.0-6.2 (1H, m), 6.71 (1H, d, J=8.1 Hz), 6.7-6.9 (1H, m), 6.96 (1H,d, J=1.6 Hz), 7.13 (2H, d, J=8.9 Hz), 7.4-7.9 (4H, m), 7.97 (2H, d,J=8.8 Hz), 8.05 (2H, d, J=9.3 Hz), 8.10 (2H, d, J=9.0 Hz), 8.6-8.8 (2H,m).

MASS (m/z): 1396.5 (M⁻−Na).

Elemental Analysis Calcd. for C₆₃H₈₆N₁₁NaO₂₁S₂.8H₂O: C, 48.36, H, 6.57,N, 9.85. Found: C, 48.50, H, 6.34, N, 9.82.

EXAMPLE 52

IR (KBr): 3392.2, 1631.5, 1504.8, 1515.8, 1442.5, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.6 Hz), 1.16 (3H, d, J=5.7 Hz),1.2-5.5 (60H, m), 5.9-6.1 (1H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H, d,J=10.0 Hz), 6.96 (1H, s), 7.13 (2H, d, J=8.8 Hz), 7.3-7.9 (4H, m), 7.97(2H, d, J=8.8 Hz), 8.0-8.2 (4H, m), 8.6-8.8 (2H, m).

MASS (m/z): 1394.4 (M⁻−Na).

EXAMPLE 53

To a mixture of starting compound (53) (100 mg) and zeolite syntheticA-4 powder (100 mg) in N,N-dimethylformamide (1 ml) was added propanesulfone (9.4 mg) and stirred for 3 days 7 hours at ambient temperature.To the reaction mixture was added ethyl acetate (20 ml). The resultingprecipitate was collected by filtration and washed with diisopropylether to give a crude white powder (104.3 mg). The crude powder waspurified by column chromatography on ODS (YMC-gel ODS-AM-S-50(Trademark: prepared by YMC Co., Ltd.)) (20% acetonitrile aqueoussolution). The fractions containing the object compound were combined,and evaporated under reduced pressure to remove acetonitrile. Theresidue was lyophilized to give object compound (53) (34.2 mg).

IR (KBr): 3372.9, 1658.5, 1635.3, 1546.6, 1529.3, 1517.7, 1444.4,1255.4, 1178.3, 1045.2 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.6 Hz), 1.13 (3H, d, J=5.8 Hz),1.2-5.5 (60H, m), 6.71 (1H, d, J=8.2 Hz), 6.77 (1H, d, J=10.0 Hz), 6.95(1H, s), 7.13 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.7 Hz), 8.09 (4H, s),7.3-9.0 (6H, m).

MASS (m/z): 1419.4 (M⁻−Na).

Elemental Analysis Calcd. for C₆₁H₈₃N₁₀NaO₂₃S₃.8H₂O: C, 46.15, H, 6.28,N, 8.82. Found: C, 46.11, H, 6.04, N, 8.74.

The following compounds [Examples 54 to 56] were obtained according to asimilar manner to that of Example 53.

EXAMPLE 54

IR (KBr): 3355.5, 2935.1, 1635.3, 1529.3, 1517.7, 1444.4, 1257.4,1178.3, 1045.2 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.12 (3H, d, J=5.3 Hz),1.2-5.4 (62H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H, d, J=9.5 Hz), 6.96(1H, s), 7.13 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.7 Hz), 8.05 (2H, d,J=8.8 Hz), 8.12 (2H, d, J=8.5 Hz), 7.3-9.0 (6H, m).

MASS (m/z): 1455.3 (M⁻−1).

EXAMPLE 55

IR (KBr): 3369.0, 1633.4, 1533.1, 1517.7, 1444.4, 1413.6, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.6 Hz), 1.14 (3H, d, J=5.7 Hz),1.2-5.4 (58H, m), 6.6-6.9 (2H, m), 6.94 (1H, s), 7.13 (2H, d, J=8.9 Hz),7.97 (2H, d, J=8.8 Hz), 8.08 (4H, s), 7.3-9.0 (6H, m).

MASS (m/z): 1391.2 (M⁻−1).

Elemental Analysis Calcd. for C₆₁H₈₁N₁₀NaO₂₂S₂.8H₂O: C, 47.65, H, 6.36,N, 9.11. Found: C, 47.52, H, 6.10, N, 8.84.

EXAMPLE 56

IR (KBr): 3363.2, 1666.2, 1648.8, 1631.5, 1538.9, 1513.8, 1450.2,1442.5, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.6 Hz), 1.12 (3H, d, J=35.6 Hz),1.2-5.6 (60H, m), 6.71 (1H, d, J=8.1 Hz), 6.77 (1H, d, J=9.1 Hz), 6.97(1H, s), 7.13 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.7 Hz), 8.06 (2H, d,J=8.6 Hz), 8.13 (2H, d, J=8.7 Hz), 7.3-9.0 (6H, m).

MASS (m/z): 1457.4 (M⁻−1).

Elemental Analysis Calcd. for C₆₁H₈₃N₁₀NaO₂₄S₃.9H₂O: C, 45.18, H, 6.28,N, 8.64. Found: C, 45.14, H, 6.11, N, 8.52.

The following compounds [Examples 57 to 58] were obtained according to asimilar manner to that of Example 18.

EXAMPLE 57

IR (KBr): 1670, 1632, 1535, 1518, 1443 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.94 (3H, d, J=6.70 Hz), 1.10 (3H, d, J=5.86 Hz),1.35 (9H, s), 1.45-1.95 (6H, m), 2.10-2.40 (2H, m), 2.80-3.45 (7H, m),3.60-4.80 (15H, m), 5.05-5.40 (2H, m), 5.70-6.05 (1H, m), 10 6.74 (1H,d, J=8.18 Hz), 6.82 (1H, d, J=10.2 Hz), 7.06 (1H, s).

ESI MASS (m/z) (Positive): 1135.2 (M⁺+Na).

Elemental Analysis Calcd. for C₄₄H₆₅N₈O₂₂SNa.4H₂O: C, 44.59, H, 6.21, N,9.45. Found: C, 44.55, H, 6.37, N, 9.39.

EXAMPLE 58

IR (KBr): 3344, 2925.5, 2854, 1664, 1635, 1529, 1518, 1446, 1277, 1252,1171, 1086, 1045 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.82-0.88 (3H, m), 0.97 (3H, d, J=6.6 Hz), 1.08(3H, d, J=5.5 Hz), 1.37 (9H, s), 1.5-4.80 (57H, complex m), 6.71-6.79(2H, m), 7.00 (1H, br s).

MASS (m/z): 1227.4 (M⁺−Na).

Elemental Analysis Calcd. for C₅₆H₉₁N₈O₂₀SNa.5H₂O: C, 50.14, H, 7.59, N,8.35. Found: C, 49.93, H, 7.51, N, 8.31.

EXAMPLE 59

A mixture of 4-[5-[4-(6-methoxyhexyloxy)phenyl]isoxazol-3-yl]benzoicacid (100 mg), 1-hydroxybenzotriazole (51.3 mg),1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (58.2 mg)and N,N-diisopropylethylamine (66.1 μl) in N,N-dimethylformamide (2 ml)was stirred for 4.5 hours. To the reaction mixture was added startingcompound (59) (246.6 mg) and stirred for overnight. To the reactionmixture was added ethyl acetate (100 ml). The resulting precipitate wascollected by filtration and washed with diisopropyl ether to give objectcompound (59) as a crude white powder (406.7 mg), that was used crude inthe next reaction.

The following compounds [Example 60 to 62] were obtained according to asimilar manner to that of Example 59.

EXAMPLE 60

The object compound (60) was used directly in the next reaction withoutpurification.

EXAMPLE 61

The object compound (61) was used directly in the next reaction withoutpurification.

EXAMPLE 62

The object compound (62) was used directly in the next reaction withoutpurification.

The following compounds [Examples 63 to 77] were obtained according to asimilar manner to that of Preparation 84.

EXAMPLE 63

IR (KBr): 3369.0, 1631.5, 1538.9, 1513.8, 1442.5, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.11 (3H, d, J=5.4 Hz),1.2-5.6 (70H, m), 6.71 (1H, d, J=8.3 Hz), 6.77 (1H, d, J=9.6 Hz), 6.99(1H, s), 7.14 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.6 Hz), 8.04 (2H, d,J=8.5 Hz), 8.11 (2H, d, J=8.3 Hz), 7.3-9.0 (6H, m).

ESI MASS (m/z): 1442.6 (M⁻−1).

Elemental Analysis Calcd. for C₆₅H₉₃N₁₁O₂₂S₂.7H₂O: C, 49.70, H, 6.87, N,9.81. Found: C, 49.43, H, 6.71, N, 9.71.

EXAMPLE 64

IR (KBr): 1633, 1606, 1527, 1518, 1466 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.11 (3H, d, J=5.6 Hz),1.2-2.5 (18H, m), 2.7-4.6 (34H, m), 4.6-5.4 (8H, m), 6.7-7.2 (5H, m),7.3-7.6 (2H, m), 7.6-7.85 (4H, m), 7.95 (4H, s), 8.2-8.4 (1H, m),8.6-8.75 (1H, m), 8.80 (1H, s).

MASS (m/z): 1407 (M⁺+1).

EXAMPLE 65

IR (KBr): 3363.2, 1666.2, 1648.8, 1631.5, 1538.9, 111. 1508.1, 1452.1,1436.7, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.8 Hz), 1.11 (3H, d, J=5.7 Hz),1.2-5.6 (53H, m), 6.71 (1H, d, J=8.1 Hz), 6.7-6.9 (1H, m), 7.01 (1H, d,J=1.6 Hz), 7.13 (2H, d, J=8.9 Hz), 7.45 (1H, d, J=8.3 Hz), 7.55 (1H, s),7.85 (2H, d, J=8.7 Hz), 7.6-7.9 (2H, m), 7.99 (2H, d, J=8.8 Hz), 8.05(2H, d, J=8.9 Hz), 8.32 (1H, d, J=7.3 Hz), 8.71 (1H, s), 8.87 (1H, d,J=7.5 Hz).

MASS (m/z): 1266.4 (M⁻−1).

Elemental Analysis Calcd. for C₅₈H₇₇N₉O₂₁S.8H₂O: C, 49.32, H, 6.64, N,8.92. Found: C, 49.42, H, 6.43, N, 8.88.

EXAMPLE 66

IR (KBr): 3490, 3463, 3424, 3357, 2935, 1633, 1542, 1519 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.6 Hz), 1.12 (3H, d, J=5.4 Hz),1.22-1.35 (6H, m), 1.35-2.40 (15H, m), 2.80-3.10 (3H, m), 3.18 (3H, s),3.25 (3H, t, J=6.4 Hz), 3.45-3.60 (3H, m), 3.65-4.60 (15H, m), 4.70-5.30(8H, m), 6.70-6.80 (2H, m), 7.00 (1H, br s), 7.40-7.75 (3H, m),8.00-8.40 (3H, m), 8.46 (2H, d, J=8.4 Hz), 8.50-9.00 (2H, m).

MASS (m/z) (API-ES-negative): 1332 (M⁺+1).

Elemental Analysis Calcd. for C₅₈H₃₈N₁₀O₂₂S₂.5H₂O: C, 49.00, H, 6.19, N,9.85. Found: C, 49.20, H, 6.15, N, 9.69.

EXAMPLE 67

IR (KBr): 3457, 3425, 3400, 3365, 2931, 1639, 1537, 1518 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.12 (3H, d, J=5.4 Hz),1.20-1.35 (12H, m), 1.35-1.70 (6H, m), 1.70-2.40 (7H, m), 2.80-3.10 (3H,m), 3.17 (3H, s), 3.26 (3H, t, J=6.4 Hz), 3.30-3.50 (3H, m), 3.65-4.10(6H, m), 4.10-4.60 (7H, m), 4.65-5.40 (8H, m), 6.60-6.80 (2H, m), 7.00(1H, br s), 7.30-7.80 (6H, m), 8.05-8.40 (7H, m), 8.47 (2H, d, J=8.4Hz), 8.71 (1H, br s), 8.93 (1H, m).

MASS (m/z) (API-ES Negative): 1360 (M⁺+1).

Elemental Analysis Calcd. for C₆₀H₈₂N₁₀O₂₂S₂.6H₂O: C, 49.08, H, 6.41, N,9.54. Found: C, 48.88, H, 6.41, N, 9.47.

EXAMPLE 68

IR (KBr): 3457, 3424, 3400, 3367, 2935, 1637, 1509, 1261 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.12 (3H, d, J=5.4 Hz),1.20-1.50 (9H, m), 1.60-2.45 (9H, m), 3.21 (3H, s), 3.30 (2H, t, J=6.5Hz), 3.40-3.90 (6H, m), 3.90-4.55 (12H, m), 4.60-5.80 (6H, m), 6.72 (1H,d, J=8.1 Hz), 6.74 (1H, dd, J=1.5 and 8.4 Hz), 7.00 (1H, d, J=1.5 Hz),7.20 (2H, d, J=8.9 Hz), 7.40-7.90 (4H, m), 8.00-8.40 (6H, m), 8.94 (1H,m).

MASS (m/z) (API-ES-Negative): 1284 (M⁺+1).

Elemental Analysis Calcd. for C₅₈H₇₈N₁₀O₂₁S.7H₂O: C, 49.40, H, 6.53, N,9.94. Found: C, 49.17, H, 6.36, N, 9.74.

EXAMPLE 69

IR (KBr): 3458, 3423, 3398, 3367, 2931, 1637, 1508, 1259 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.12 (3H, d, J=5.5 Hz),1.20-1.60 (12H, m), 1.65-2.45 (9H, m), 2.80-3.15 (3H, m), 3.20 (3H, s),3.29 (3H, t, J=6.5 Hz), 3.80-4.50 (17H, m), 4.60-5.30 (8H, m), 6.71 (1H,d, J=8.2 Hz), 6.69-6.80 (1H, m), 7.00 (1H, br s), 7.20 (2H, d, J=8.9Hz), 7.30-7.90 (7H, m), 8.05-8.40 (8H, m), 8.60-9.00 (2H, m).

MASS (m/z) (API-ES-Negative): 1312 (M⁺+1).

Elemental Analysis Calcd. for C₆₀H₈₂N₁₀O₂₁S.6H₂O: C, 50.74, H, 6.62, N,9.87. Found: C, 50.48, H, 6.56, N, 9.60.

EXAMPLE 70

IR (KBr): 3372.9, 1664.3, 1635.3, 1361.5, 1444.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.12 (3H, d, J=5.8 Hz),1.2-5.3 (55H, m), 6.71 (1H, d, J=8.1 Hz), 6.7-6.9 (1H, m), 7.00 (1H, d,J=1.6 Hz), 7.12 (2H, d, J=8.9 Hz), 7.45 (1H, d, J=8.6 Hz), 7.54 (1H, s),7.6-7.8 (2H, m), 7.85 (2H, d, J=8.7 Hz), 7.99 (2H, d, J=8.7 Hz), 8.05(2H, d, J=8.9 Hz), 8.25 (1H, d, J=6.7 Hz), 8.81 (1H, d, J=7.4 Hz).

MASS (m/z): 1280.4 (M⁻−1).

Elemental Analysis Calcd. for C₅₉H₇₉N₉O₂₁S.6H₂O: C, 50.96, H, 6.60, N,9.07. Found: C, 50.89, H, 6.43, N, 8.98.

EXAMPLE 71

IR (KBr): 3371.0, 1631.5, 1538.9, 1506.1, 1450.2, 1436.7, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.2 (12H, m), 1.2-5.5 (58H, m), 6.71 (1H, d, J=8.1Hz), 6.7-6.9 (1H, m), 7.01 (1H, d, J=1.7 Hz), 7.12 (2H, d, J=8.9 Hz),7.45 (1H, d, J=9.2 Hz), 7.54 (1H, s), 7.5-7.9 (2H, m), 7.85 (2H, d,J=8.8 Hz), 7.99 (2H, d, J=8.8 Hz), 8.05 (2H, d, J=8.9 Hz), 8.1-8.4 (1H,m), 8.70 (1H, m), 8.86 (1H, d, J=7.8 Hz).

MASS (m/z): 1363.5 (M⁻−1).

Elemental Analysis Calcd. for C₆₄H₈₈N₁₀O₂₁S.7H₂O: C, 51.53, H, 6.89, N,9.39. Found: C, 51.23, H, 6.80, N, 9.27.

EXAMPLE 72

IR (KBr): 3363.2, 1666.2, 1648.8, 1538.9, 1506.1, 1454.1, 1436.7, 1257.4cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.2 (12H, m), 1.2-5.3 (60H, m), 6.71 (1H, d, J=8.2Hz), 6.7-6.9 (1H, m), 7.01 (1H, s), 7.12 (2H, d, J=8.9 Hz), 7.54 (1H,s), 7.3-7.8 (3H, m), 7.85 (2H, d, J=8.7 Hz), 7.9-8.2 (4H, m), 8.2-8.4(1H, m), 8.7 (1H, s), 8.8-9.0 (1H, m).

MASS (m/z): 1377.6 (M⁻−1).

Elemental Analysis Calcd. for C₆₅H₉₀N₁₀O₂₁S.8H₂O: C, 51.24, H, 7.01, N,9.19. Found: C, 51.52, H, 7.06, N, 9.16.

EXAMPLE 73

IR (KBr): 3363.2, 1631.5, 1538.9, 1510.0, 1438.6, 1243.9 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.11 (3H, d, J=5.7 Hz), 1.18(6H, d, J=6.0 Hz), 1.2-5.5 (44H, m), 6.71 (1H, d, J=8.2 Hz), 6.78 (1H,d, J=9.8 Hz), 7.00 (1H, s), 7.11 (2H, d, J=8.9 Hz), 7.46 (1H, s),7.3-7.8 (3H, m), 7.76 (2H, d, J=8.7 Hz), 7.99 (2H, d, J=8.6 Hz), 8.05(2H, d, J=8.7 Hz), 8.2-9.0 (3H, m).

MASS (m/z): 1249.4 (M⁻−1).

EXAMPLE 74

MASS (m/z): 1377.4 (M⁺−1).

EXAMPLE 75

MASS (m/z): 1405.4 (M⁺−1).

EXAMPLE 76

NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6.3 Hz), 0.98 (3H, d, J=6.8 Hz), 1.11(3H, d, J=5.8 Hz), 1.20-5.23 (56H, m), 6.69-8.93 (17H, m).

MASS (m/z): 1333.4 (M⁺−1).

EXAMPLE 77

MASS (m/z): 1297.3 (M⁺−1).

EXAMPLE 78

A mixture of starting compound (78) (100 mg),N-tert-butoxycarbonyl-β-alanine (13.5 mg), 1-hydroxybenzotriazole (15.5mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (29.4mg) and N,N-diisopropylethylamine (28.2 μl) in N,N-dimethylformamide (1ml) was stirred for 3 hours at 30° C. To the reaction mixture was addedethyl acetate (30 ml). The resulting precipitate was collected byfiltration and washed with diisopropyl ether to give a crude whitepowder (137.3 mg). The crude powder was purified by columnchromatography on ODS (YMC-gel ODS-AM-S-50 (Trademark: prepared by YMCCo., Ltd.)) (30% acetonitrile aqueous solution). The fractionscontaining the object compound were combined, and evaporated underreduced pressure to remove acetonitrile. The residue was lyophilized togive object compound (78).

IR (KBr): 3372.9, 1658.5, 1635.3, 1546.8, 1529.3, 1517.7, 1444.4, 1255.4cm⁻¹.

MASS (m/z): 1468.3 (M⁻−Na).

Elemental Analysis Calcd. for C₆₆H₉₀N₁₁NaO₂₃S₂.6H₂O: C, 49.52, H, 6.42,N, 9.63. Found: C, 49.34, H, 6.33, N, 9.73.

The following compounds [Examples 79 to 86] were obtained according to asimilar manner to that of Example 78.

EXAMPLE 79

IR (KBr): 3374.8, 1658.5, 1635.3, 1529.3, 1517.7, 1444.4, 1257.4 cm⁻¹.

MASS (m/z): 1368.3 (M⁻−Na).

EXAMPLE 80

IR (KBr): 3372.9, 1656.6, 1635.3, 1531.2, 1517.7, 1444.4, 1255.4 cm⁻¹.

MASS (m/z): 1496.4 (M⁻−Na).

Elemental Analysis calcd. for C₆₈H₉₄N₁₁NaO₂₃S₂.6H₂O: C, 50.15, H, 6.56,N, 9.46. Found: C, 49.90, H, 6.36, N, 9.34.

EXAMPLE 81

IR (KBr): 3392.2, 1664.3, 1635.3, 1446.4, 1255.4 cm⁻¹.

MASS (m/z): 1611.5 (M⁻−Na).

Elemental Analysis Calcd. for C₇₃H₁₀₃N₁₂NaO₂₅S₂.7H₂O: C, 49.76, H, 6.69,N, 9.54. Found: C, 49.73, H, 6.59, N, 9.46.

EXAMPLE 82

IR (KBr): 3372.9, 1658.5, 1635.3, 1546.6, 1531.2, 1517.7, 1444.4, 1255.4cm⁻¹.

MASS (m/z): 1498.5 (M⁻−Na).

Elemental Analysis Calcd. for C₆₇H₉₂N₁₁NaO₂₄S₂.8H₂O: C, 48.28, H, 6.53,N, 9.24. Found: C, 48.50, H, 6.35, N, 9.21.

EXAMPLE 83

IR (KBr): 3378.7, 1658.5, 1635.3, 1546.6, 1529.3, 1517.7, 1446.4, 1255.4cm⁻¹.

MASS (m/z): 1625.5 (M⁻−Na).

Elemental Analysis Calcd. for C₇₄H₁₀₅N₁₂NaO₂₅S₂.8H₂O: C, 49.55, H, 6.80,N, 9.37. Found: C, 49.70, H, 6.68, N, 9.38.

EXAMPLE 84

IR (KBr): 3367.7, 1658.5, 1635.3, 1546.6, 1529.3, 1517.7, 1444.4, 1255.4cm⁻¹.

MASS (m/z): 1634.6 (M⁻−Na).

Elemental Analysis Calcd. for C₇₄H₁₀₀N₁₃NaO₂₅S₂.7H₂O: C, 49.80, H, 6.44,N, 10.20. Found: C, 49.71, H, 6.34, N, 10.29.

EXAMPLE 85

IR (KBr): 3355.5, 1658.5, 1635.3, 1546.6, 1531.2, 1517.7, 1446.4, 1257.4cm⁻¹.

MASS (m/z): 1693.5 (M⁻−Na).

Elemental Analysis Calcd. for C₈₀H₁₀₁N₁₂NaO₂₅S₂.7H₂O: C, 52.11, H, 6.29,N, 9.12. Found: C, 51.96, H, 6.28, N, 9.06.

EXAMPLE 86

IR (KBr): 3372.9, 1658.5, 1635.3, 1546.6, 1531.2, 1517.7, 1446.4, 1257.4cm⁻¹.

MASS (m/z): 1645.4 (M⁻−Na).

Elemental Analysis Calcd. for C₇₆H₁₀₁N₁₂NaO₂₅S₂.8H₂O: C, 52.32, H, 6.50,N, 9.27. Found: C, 50.56, H, 6.37, N, 9.29.

The following compounds [Examples 87 to 95] were obtained according to asimilar manner to that of Preparation 10.

EXAMPLE 87

IR (KBr): 2935, 1651, 1541, 1514, 1454, 1514, 1257 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.97 (3H, d, J=6.7 Hz), 1.12 (3H, br s), 1.20-5.00(44H, m), 3.21 43H, s), 3.31 (2H, t, J=6.4 Hz), 4.07 (2H, t, J=6.2 Hz),6.70-6.80 (2H, m), 7.00 (1H, s), 7.14 (2H, d, J=8.9 Hz), 7.98 (2H, d,J=8.9 Hz), 8.09 (4H, br s).

MASS (m/z): 1443.3 (M⁺+Na).

Elemental Analysis Calcd. for C₆₂H₈₁N₁₀O₂₃S₂Na.7H₂O: C, 48.12, H, 6.19,N, 9.05. Found: C, 47.94, H, 6.07, N, 8.99.

EXAMPLE 88

MASS (m/z): 1492 (M⁺).

EXAMPLE 89

IR (KBr): 3490, 3463, 3455, 3423, 3363, 2937, 1631, 1544 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.6 Hz), 1.21 (3H, d, J=5.4 Hz),1.20-1.40 (9H, m), 1.40-2.40 (12H, m), 2.90-3.20 (3H, m), 3.21 (3H, s),3.33 (3H, t, J=6.4 Hz), 3.65-4.30 (9H, m), 4.40-5.00 (6H, m), 5.11-5.30(6H, m), 5.80-6.10 (1H, m), 6.69-6.80 (2H, m), 6.96 (1H, br s), 7.13(1H, br s), 7.40-7.90 (3H, m), 8.00-8.30 (7H, m), 8.47 (2H, d, J=8.3Hz), 8.72 (1H, br s), 8.75-8.90 (1H, m).

MASS (m/z) (API-ES-Negative): 1415 (M⁺−1−Na).

Elemental Analysis Calcd. for C₆₂H₈₁N₁₀NaO₂₄S₂.2.5H₂O: C, 50.20, H,5.80, N, 9.45. Found: C, 50.05, H, 5.80, N, 9.29.

EXAMPLE 90

IR (KBr): 3369, 1639, 1542, 1519, 1272 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.14 (3H, d, J=5.8 Hz),1.20-1.35 (12H, m), 1.35-1.70 (6H, m), 1.70-2.40 (6H, m), 3.17 (3H, s),3.25 (3H, t, J=6.3 Hz), 3.30-3.50 (2H, m), 3.60-4.30 (9H, m), 4.40-4.90(6H, m), 5.10-5.30 (6H, m), 5.80-5.90 (1H, m), 6.71 (1H, d, J=8.2 Hz),6.60-6.80 (1H, m), 6.96 (1H, br s), 7.00-7.20 (1H, m), 7.40-7.90 (3H,m), 8.00-8.20 (6H, m), 8.48 (2H, d, J=8.4 Hz), 8.72 (1H, br s), 8.70-8.8(1H, m).

MASS (m/z): 1441 (M⁺−1−Na).

Elemental Analysis Calcd. for C₆₄H₈₅N₁₀NaO₂₄S₂.6H₂O: C, 48.82, H, 6.17,N, 8.90. Found: C, 48.83, H, 6.24, N, 8.78.

EXAMPLE 91

IR (KBr): 3363, 2935, 1637, 1626, 1540, 1261 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.13 (3H, d, J=5.8 Hz),1.30-1.60 (12H, m), 1.70-2.50 (7H, m), 2.80-3.25 (3H, m), 3.21 (3H, s),3.30 (2H, t, J=6.5 Hz), 3.65-4.30 (12H, m), 4.40-5.00 (9H, m), 5.10-5.40(7H, m), 5.80-6.05 (1H, m), 6.71 (1H, d, J=8.1 Hz), 6.75 (1H, dd, J=8.3and 1.6 Hz), 6.96 (1H, d, J=1.6 Hz), 7.10 (1H, br s), 7.20 (1H, d, J=8.8Hz), 7.40-7.80 (3H, m), 8.00-8.20 (7H, m), 8.72 (1H, br s), 8.70-8.80(1H, m).

MASS (m/z) (API-ES-Negative): 1367 (M⁺+1−Na).

Elemental Analysis Calcd. for C₆₂H₈₁N₁₀NaO₂₃S.6H₂O: C, 69.70, H, 6.21,N, 9.35. Found: C, 49.86, H, 6.22, N, 9.35.

EXAMPLE 92

IR (KBr): 3363, 2933, 2859, 1637, 1540, 1510, 1444, 1261 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.13 (3H, d, J=5.8 Hz),1.28-1.60 (15H, m), 1.69-2.45 (8H, m), 2.80-3.30 (3H, m), 3.20 (3H, s),3.26 (2H, t, J=6.4 Hz), 3.60-4.30 (12H, m), 4.40-5.00 (9H, m), 5.10-5.30(7H, m), 5.75-6.05 (1H, m), 6.68 (1H, d, J=8.1 Hz), 6.75 (1H, dd, J=1.7and 8.3 Hz), 6.96 (1H, d, J=1.7 Hz), 7.10-7.20 (1H, m), 7.15 (2H, d,J=8.9 Hz), 7.40-7.90 (3H, m), 8.00-8.20 (7H, m), 8.60-8.80 (2H, m).

MASS (m/z) (APCI-ES-Negative): 1395 (M⁺+1−Na).

Elemental Analysis Calcd. for C₆₄H₈₅N₁₀NaO₂₃S.6H₂O: C, 50.36, H, 6.36,N, 9.18. Found: C, 50.22, H, 6.31, N, 9.10.

EXAMPLE 93

MASS (m/z): 1461.4 (M⁺−1).

EXAMPLE 94

MASS (m/z): 1489.5 (M⁺−1).

EXAMPLE 95

NMR (DMSO-d₆, δ): 0.87 (3H, d, J=6.3 Hz), 0.97 (3H, d, J=6.7 Hz),1.14-5.29 (81H, m), 6.69-8.72 (18H, m).

MASS (m/z): 1418.4 (free).

The following compounds [Examples 96 to 117] were obtained according toa similar manner to that of Example 19.

EXAMPLE 96

IR (KBr): 1632, 1539, 1520, 1443 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.97 (3H, d, J=6.64 Hz), 1.07 (3H, d, J=5.68 Hz),1.15-1.70 (3H, m), 1.70-2.50 (5H, m), 2.70-3.40 (5H, m), 4.10-4.60 (8H,m), 4.70-4.85 (2H, m), 5.00-5.35 (2H, m), 5.70-6.10 (1H, m), 6.50-6.80(2H, m), 6.99 (1H, s).

ESI MASS (m/z) (Positive): 1019.3 (M⁺+Na).

Elemental Analysis Calcd. for C₃₉H₅₇N₈O₁₉SNa.8H₂O: C, 41.05, H, 6.45, N,9.82. Found: C, 41.02, H, 6.19, N, 9.73.

EXAMPLE 97

IR (KBr): 1647, 1635, 1539, 1518, 1439, 1269 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.95 (3H, d, J=6.66 Hz), 1.12 (3H, d, J=5.76 Hz),1.20-1.60 (4H, m), 1.70-2.45 (4H, m), 2.65-3.35 (6H, m), 3.70-4.55 (16H,m), 4.60-4.80 (2H, m), 5.10-5.40 (2H, m), 5.70-6.00 (1H, m), 6.75 (1H,d, J=8.15 Hz), 6.83 (1H, d, J=10.1 Hz), 7.09 (1H, s).

ESI MASS (m/z) (Negative): 989.3 (M⁺).

Elemental Analysis Calcd. for C₃₉H₅₈N₈O₂₀SNa.5H₂O: C, 43.33, H, 6.34, N,10.37. Found: C, 43.17, H, 6.25, N, 10.30.

EXAMPLE 98

IR (KBr): 1680, 1662, 1639, 1539, 1514, 1439 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.98 (3H, d, J=6.77 Hz), 1.09 (3H, d, J=6.01 Hz),1.15-1.40 (1H, m), 1.45-2.00 (4H, m), 2.10-2.50 (4H, m), 2.70-2.90 (3H,m), 3.15-3.40 (4H, m), 3.70-4.00 (6H, m), 4.10-4.50 (6H, m), 4.75-4.80(2H, m), 6.70-6.80 (2H, m), 7.03 (1H, s).

ESI MASS (m/z) (Positive): 892.2 (M⁺+1).

Elemental Analysis Calcd. for C₃₅H₅₄N₈O₁₇S.4H₂O: C, 43.65, H, 6.49, N,11.64. Found: C, 43.51, H, 6.40, N, 11.48.

EXAMPLE 99

NMR (DMSO-d₆+D₂O, δ): 0.96 (3H, d, J=6.69 Hz), 1.09 (3H, d, J=5.05 Hz),1.15-2.40 (8H, m), 2.65-3.30 (3H, m), 3.70-4.90 (18H, m), 6.65-6.85 (2H,m), 6.99 (1H, s).

ESI MASS (m/z) (Positive): 1013.4 (M⁺+Na).

EXAMPLE 100

IR (KBr): 3377, 2935, 1658.5, 1641, 1531, 1518, 1444, 1284, 1257, 1113,1088, 1043 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.05 (3H, d, J=5.6 Hz), 3.21(3H, s), 4.07 (2H, t, J=6.5 Hz), 1.2-5.2 (571, complex m), 6.70 (1H, d,J=8.1 Hz), 6.78-6.83 (1H, m), 6.99 (1H, br s), 7.13 (2H, d, J=8.8 Hz),7.4-7.6 (2H, m), 7.7-7.9 (1H, m), 7.97 (2H, d, J=8.8 Hz), 8.09 (4H, s),8.50-8.60 (1H, m), 8.71 (1H, s), 8.68-8.80 (1H, m).

MASS (m/z): 14,07.3 (M⁺).

Elemental Analysis Calcd. for C₆₄H₈₅N₁₁O₂₁S₂.7H₂O: C, 50.09, H, 6.50, N,10.04. Found: C, 50.01, H, 6.41, N, 9.91.

EXAMPLE 101

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.8 Hz), 1.1-5.6 (72H, m), 6.6-6.9 (2H,m), 6.99 (1H, s), 7.14 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.7 Hz), 8.08(4H, s), 7.4-9.0 (6H, m).

MASS (m/z): 1411.3 (M⁻−1).

EXAMPLE 102

IR (KBr): 3384.5, 1658.5, 1635.3, 1444.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.14 (3H, d, J=5.3 Hz),1.3-5.4 (62H, m), 6.70 (1H, d, J=8.2 Hz), 6.77 (1H, d, J=9.8 Hz), 6.96(1H, s), 7.13 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.8 Hz), 8.05 (2H, d,J=8.83 Hz), 8.11 (2H, d, J=8.9 Hz), 7.4-9.0 (6H, m).

MASS (m/z): 1354.3 (M⁻−1).

EXAMPLE 103

IR (KBr): 3401.8, 1664.3, 1635.3, 1627.6, 1446.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.8 Hz), 1.0-5.6 (69H, m), 6.68 (1H, d,J=8.1 Hz), 6.78 (1H, d, J=8.7 Hz), 6.93 (1H, d, J=8.4 Hz), 7.13 (2H, d,J=8.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.08 (4H, s), 7.4-9.0 (6H, m).

MASS (m/z): 1382.4 (M⁻−1).

EXAMPLE 104

IR (KBr): 3403.7, 1664.3, 1635.3, 1446.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.6 Hz), 1.0-5.5 (71H, m), 7.13 (2H, d,J=8.9 Hz), 7.97 (2H, d, J=8.8 Hz), 6.6-8.9 (13H, m).

MASS (m/z): 1420.2 (M⁺+Na).

EXAMPLE 105

IR (KBr): 3367.1, 1635.3, 1531.2, 1517.7, 1444.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.12 (3H, d, J=5.9 Hz),1.2-5.4 (64H, m), 6.70 (1H, d, J=8.1 Hz), 6.77 (1H, d, J=10.0 Hz), 6.99(1H, s), 7.14 (2H, d, J=8.9 Hz), 7.44 (1H, d, J=8.6 Hz), 7.62 (1H, m),7.78 (1H, m), 7.97 (2H, d, J=8.8 Hz), 8.05 (2H, d, J=8.8 Hz), 8.11 (2H,d, J=8.7 Hz), 8.1-8.3 (1H, m), 8.6-8.9 (2H, m).

MASS (m/z): 1368.5 (M⁻−1).

Elemental Analysis Calcd. for C₆₂H₈₇N₁₁O₂₀S₂.8H₂O: C, 49.16, H, 6.85, N,10.17. Found: C, 49.29, H, 6.50, N, 10.08.

EXAMPLE 106

IR (KBr): 2935.1, 2865.7, 1648.8, 1538.9, 1513.8, 1452.1, 1440.6, 1257.4cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.97 (3H, d, J=6.3 Hz), 1.11 (3H, d, J=5.7 Hz),1.2-4.9 (55H, complex m), 3.21 (3H, s), 3.31 (2H, t, J=6.5 Hz), 6.7-6.81(2H, m), 7.03 (1H, br s), 7.14 (2H, d, J=8.9 Hz), 7.98 (2H, d, J=8.9Hz), 8.0-8.15 (4H, m).

MASS (m/z): 1463.4 (M⁺−1).

Elemental Analysis Calcd. for C₆₇H₉₂N₁₂O₂₁S₂.7H₂O: C, 50.56, H, 6.71, N,10.56. Found: C, 50.34, H, 6.38, N, 10.46.

EXAMPLE 107

IR (KBr): 2933, 2860, 1657, 1635, 1529, 1516, 1444, 1387, 1257, 1178,1115, 1088, 1043 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.97 (3H, d, J=6.7 Hz), 1.12 (3H, d, J=5.9 Hz),1.4-4.85 (50H, complex m), 3.21 (3H, s), 3.31 (2H, t, J=6.3 Hz), 6.7-6.8(2H, m), 7.02 (1H, br s), 7.14 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.9Hz), 8.02-8.14 (4H, m).

MASS (m/z): 1381.4 (M⁺−1).

Elemental Analysis Calcd. for C₆₃H₈₇N₁₁O₂₀S₂.6H₂O: C, 50.76, H, 6.69, N,10.34. Found: C, 50.43, H, 6.70, N, 10.20.

EXAMPLE 108

IR (KBr): 2935, 2866, 1660, 1631.5, 1525, 1442.5, 1412, 1257, 1178,1111, 1088, 1043 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.5 Hz),1.2-4.9 (55H, complex m), 3.21 (3H, s), 3.31 (2H, t, J=6.4 Hz), 6.75(2H, br), 7.05 (1H, br), 7.14 (2H, d, J=8.8 Hz), 7.99 (2H, d, J=8.8 Hz),8.01-8.16 (4H, m).

MASS (m/z): 1510.5 (M⁺−1).

Elemental Analysis Calcd. for C₆₈H₉₄N₁₂O₂₃S₂.7H₂O: C, 49.87, H, 6.65, N,10.26. Found: C, 49.64, H, 6.57, N, 10.15.

EXAMPLE 109

IR (KBr): 3372.9, 1658.5, 1635.3, 1529.3, 1517.7, 1446.4, 1255.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.15 (3H, d, J=5.1 Hz),1.2-5.6 (58H, m), 6.71 (1H, d, J=8.1 Hz), 6.77 (1H, d, J=10.0 Hz), 6.97(1H, s), 7.13 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.8 Hz), 8.09 (4H, s),7.3-9.0 (7H, m).

MASS (m/z): 1510.5 (M⁻−Na).

Elemental Analysis Calcd. for C₆₁H₈₂N₁₁NaO₂₁S₂.8H₂O: C, 47.68, H, 6.43,N, 10.03. Found: C, 49.75, H, 6.19, N, 10.23.

EXAMPLE 110

IR (KBr): 3374.8, 1656.5, 1635.3, 1529.3, 1517.7, 1444.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.8 Hz), 1.13 (3H, d, J=5.6 Hz),1.2-5.4 (64H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H, d, J=10.0 Hz), 7.03(1H, s), 7.13 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.7 Hz), 8.0-8.2 (4H,m), 7.3-9.0 (7H, m).

MASS (m/z): 1410.54 (M⁻−Na).

Elemental Analysis Calcd. for C₆₄H₈₈N₁₁NaO₂₁S₂.6H₂O: C, 49.83, H, 6.53,N, 9.99. Found: C, 49.72, H, 6.40, N, 9.99.

EXAMPLE 111

IR (KBr): 3374.8, 1658.5, 1635.3, 1546.6, 1531.2, 1517.7, 1444.4, 1257.4cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.14 (3H, d, J=5.4 Hz),1.2-5.6 (62H, m), 6.71 (1H, d, J=8.2 Hz), 6.78 (1H, d, J=9.8 Hz), 7.02(1H, s), 7.13 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.8 Hz), 8.06 (2H, d,J=9.1 Hz), 8.11 (2H, d, J=8.8 Hz), 7.3-9.0 (7H, m).

MASS (m/z): 1396.4 (M⁻−Na).

Elemental Analysis Calcd. for C₆₃H₈₆N₁₁NaO₂₁S₂.7H₂O: C, 48.92, H, 6.52,N, 9.96. Found: C, 48.92, H, 6.32, N, 9.85.

EXAMPLE 112

IR (KBr): 3359.4, 1658.5, 1635.3, 1546.6, 1531.2, 1517.7, 1444.4, 1257.4cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.6 Hz), 1.16 (3H, d, J=35.8 Hz),1.2-5.8 (64H, m), 6.71 (1H, d, J=8.1 Hz), 6.77 (1H, d, J=9.7 Hz), 6.98(1H, s), 7.13 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.7 Hz), 8.08 (4H, s),7.3-9.0 (7H, m).

MASS (m/z): 1411.4 (M⁻−Na).

Elemental Analysis Calcd. for C₆₃H₈₅N₁₂NaO₂₁S₂.7₂O: C, 48.45, H, 6.52,N, 10.76. Found: C, 48.44, H, 6.32, N, 10.62.

EXAMPLE 113

IR (KBr): 3374.8, 1658.5, 1635.3, 1546.6, 1531.2, 1517.7, 1444.4, 1257.4cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.5 Hz), 1.11 (3H, d, J=4.5 Hz),1.2-5.8 (60H, m), 6.68 (1H, d, J=8.0 Hz), 6.80 (1H, d, J=7.9 Hz), 6.93(1H, d, J=9.5 Hz), 7.13 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.7 Hz), 8.08(4H, s), 7.3-9.0 (7H, m).

MASS (m/z): 1398.4 (M⁻−Na).

EXAMPLE 114

IR (KBr): 3374.8, 1658.5, 1635.3, 1546.6, 1531.2, 1517.7, 1444.4, 1257.4cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.5 Hz), 1.15 (3H, d, J=5.8 Hz),1.2-5.6 (65H, m), 6.70 (1H, d, J=8.2 Hz), 6.77 (1H, d, J=9.8 Hz), 6.97(1H, s), 7.13 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.7 Hz), 8.08 (4H, s),7.3-9.0 (7H, m).

MASS (m/z): 1398.4 (M⁻−Na).

Elemental Analysis Calcd. for C₆₄H₈₉N₁₂NaO₂₁S₂.9H₂O: C, 47.69, H, 6.69,N, 10.43. Found: C, 47.78, H, 6.32, N, 10.17.

EXAMPLE 115

MASS (m/z): 1434.4 (M⁻−Na).

EXAMPLE 116

IR (KBr): 3348, 1658.5, 1633 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.82-0.89 (3H, m), 0.95-1.03 (6H, m), 1.1-4.78(57H, complex m), 6.7-6.8 (2H, m), 7.03 (1H, br s).

MASS (m/z): 1128.5 (M⁺−1).

Elemental Analysis Calcd. for C₅₁H₈₄N₈O₁₈S.5H₂O: C, 50.23, H, 7.77, N,9.19. Found: C, 50.10, H, 7.78, N, 9.09.

EXAMPLE 117

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.6 Hz), 1.10 (3H, d, J=5.4 Hz),0.74-2.69 (22H, m), 2.80-3.05 (3H, m), 3.15-4.62 (18H, m), 4.68-5.35(8H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H, d, J=8.1 Hz), 7.01 (1H, s),7.12 (2H, d, J=8.6 Hz), 7.37-8.10 (3H, m), 7.73 (4H, d, J=8.5 Hz), 7.97(2H, d, J=8.3 Hz), 8.22-8.40 (1H, m), 6.65-8.88 (2H, m).

MASS (m/z): 1224.4 (M⁺−1).

EXAMPLE 118

To a solution of a mixture of starting compound (118) (440 mg),1-1-dimethyl-4-oxo-piperidinium Iodide (122 mg) and acetic acid (55 μl)in a mixture of methanol (6 ml) and DMF (3 ml) was added sodiumcyanoborohydride (30 mg) with stirring at ambient temperature, and themixture was stirred at the same temperature overnight. To the reactionmixture was added ethyl acetate and the resulting precipitates werecollected by filtration and dried in vacuo. The precipitates weredissolved in a mixture of pH 6.86 standard buffer solution andacetonitrile , and the solution was subjected to column chromatographyon ODS (Daiso-gel, SP-120-40/60-ODS-B (Trademark: prepared by Daiso Co.,Ltd.)) eluting with 30% acetonitrile in water. The fractions containingthe object compound were collected and evaporated under reduced pressureto remove acetonitrile. The residue was lyophilized to give objectcompound (118) (350 mg).

IR (KBr): 3353, 2942, 1673, 1633, 1517, 1463, 1438, 1268, 1232, 1201,1135, 1085, 1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.3-1.6 (6H, m), 1.6-2.7 (17H, m), 2.7-4.2 (37H, m), 4.2-4.6 (7H, m),4.80 (2H, d, J=6.7 Hz), 5.2 (1H, m), 5.4 (1H, m), 6.77 (2H, m), 7.05(1H, s), 7.08 (2H, d, J=8.3 Hz), 7.45 (1H, d, J=8.8 Hz), 7.56 (1H, d,J=7.5 Hz), 7.75 (2H, d, J=8.8 Hz), 7.90 (1H, m), 7.96 (4H, s), 8.40 (1H,d, J=7.2 Hz), 8.6 (1H, m), 8.70 (1H, d, J=6.9 Hz), 8.79 (1H, s).

MASS (m/z): 1513.3 (M⁺+Na).

The following compounds [Examples 119 to 137] were obtained according toa similar manner to that of Example

EXAMPLE 119

IR (KBr): 3353, 2937, 1673, 1635, 1529, 1517, 1463, 1436, 1230, 1199,1133, 1085, 1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz), 1.30(4H, m), 1.50 (6H, m), 1.6-2.7 (17H, m), 2.7-4.2 (37H, m), 4.2-4.6 (7H,m), 4.80 (2H, d, J=6.7 Hz), 5.14 (1H, m), 5.35 (1H, m), 6.72 (1H, d,J=8.8 Hz), 6.80 (1H, d, J=8.8 Hz), 7.05 (1H, s), 7.08 (2H, d, J=8.8 Hz),7.45 (1H, d, J=8.8 Hz), 7.56 (1H, d, J=7.5 Hz), 7.75 (2H, d, J=8.8 Hz),7.91 (1H, m), 7.96 (4H, s), 8.40 (1H, d, J=7.2 Hz), 8.6 (1H, m), 8.70(1H, d, J=6.9 Hz), 8.80 (1H, s).

MASS (m/z): 1541.6 (M⁺+Na).

Elemental Analysis Calcd. for C₇₁H₉₉N₁₃O₂₀S₂.2TFA.9H₂O: C, 47.19, H,6.28, N, 9.54. Found: C, 47.13, H, 6.01, N, 9.47.

EXAMPLE 120

IR (KBr): 3355, 2937, 1673, 1635, 1529, 1519, 1444, 1276, 1253, 1201,1135, 1085, 1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.7 Hz), 0.98 (3H, d, J=6.7 Hz), 1.10(3H, d, J=5.7 Hz), 1.56 (5H, m), 1.6-2.7 (17H, m), 2.8-3.8 (26H, m),3.8-4.2 (9H, m), 4.2-4.6 (7H, m), 4.8 (3H, m), 5.17 (1H, m), 5.4 (1H,m), 6.71 (1H, d, J=8.2 Hz), 6.80 (1H, d, J=8.2 Hz), 7.05 (1H, s), 7.20(2H, d, J=8.8 Hz), 7.44 (1H, d, J=7.8 Hz), 7.62 (1H, d, J=7.8 Hz), 7.8(1H, m), 7.93 (2H, d, J=8.8 Hz), 8.07 (2H, d, J=8.8 Hz), 8.11 (2H, d,J=8.8 Hz), 8.30 (1H, d, J=7.8 Hz), 8.67 (1H, m), 8.85 (1H, d, J=7.8 Hz).

MASS (m/z): 1465.9 (M⁺+Na).

Elemental Analysis Calcd. for C₆₈H₉₅N₁₃O₁₈S₂.4TFA.8H₂O: C, 44.60, H,5.66, N, 8.90. Found: C, 44.70, H, 5.59, N, 8.95.

EXAMPLE 121

IR (KBr): 3355.5, 1635.3, 1533.1, 1515.8, 1417.4, 1257.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.6 Hz), 1.14 (3H, d, J=5.4 Hz),1.2-5.6 (68H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H, d, J=9.5 Hz), 7.02(1H, s), 7.14 (2H, d, J=8.8 Hz), 7.97 (2H, d, J=8.7 Hz), 8.05 (2H, d,J=8.6 Hz), 8.10 (2H, d, J=8.5 Hz), 7.4-9.0 (6H, m).

MASS (m/z): 1432.4 (M⁺+Na).

Elemental Analysis Calcd. for C₆₅H₉₁N₁₁O₂₀S₂.7H₂O: C, 50.80, H, 6.89, N,10.03. Found: C, 50.59, H, 6.84, N, 10.00.

EXAMPLE 122

IR (KBr): 3374.8, 1648.8, 1631.5, 1538.9, 1513.8, 1450.2, 1442.5, 1257.4cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.8 Hz), 1.0-5.4 (65H, m), 6.6-6.9 (2H,m), 7.00 (1H, s), 7.14 (2H, d, J=8.4 Hz), 7.97 (2H, d, J=8.2 Hz), 8.05(2H, d, J=8.7 Hz), 8.11 (2H, d, J=8.2 Hz), 7.3-9.0 (7H, m).

MASS (m/z): 1429.3 (M⁻−1).

Elemental Analysis Calcd. for C₆₃H₈₆N₁₀O₂₂S₃.5H₂O: C, 49.73, H, 6.36, N,9.20. Found: C, 49.56, H, 6.74, N, 9.18.

EXAMPLE 123

IR (KBr): 2935, 2864, 1649, 1539, 1514, 1450, 1442.5, 1257 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.98 (3H, d, J=6.7 Hz), 1.12 (3H, d, J=5.7 Hz),1.2-4.9 (46H, complex m), 3.21 (3H, s), 3.31 (2H, t, J=6.4 Hz), 5.63(1H, s), 6.7-6.8 (2H, m), 7.02 (1H, br s), 7.15 (2H, d, J=8.8 Hz), 7.32(5H, s), 7.97 (2H, d, J=8.8 Hz), 8.06 (4H, s).

MASS (m/z): 1460.4 (M⁺).

Elemental Analysis Calcd. for C₆₈H₈₈N₁₀O₂₂S₂.6H₂O: C, 52.03, H, 6.42, N,8.92. Found: C, 51.77, H, 6.39, N, 8.77.

EXAMPLE 124

IR (KBr): 2935, 1664.3, 1631.5, 1606.4, 1442.5, 1411.6 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.97 (3H, d, J=6.8 Hz), 1.07 (3H, d, J=5.4 Hz),1.33 (6H, d, J=6.3 Hz), 1.32-4.81 (46H, complex m), 3.21 (3H, s), 3.31(2H, t, J=6.5 Hz), 6.7-6.8 (2H, m), 7.03 (1H, br s), 7.14 (2H, d, J=8.8Hz), 7.98 (2H, d, J=8.8 Hz), 8.08 (4H, s).

MASS (m/z): 1411.5 (M⁺−1). Elemental Analysis Calcd. forC₆₄H₈₈N₁₀O₂₂S₂.5H₂O: C, 51.12, H, 6.57, N, 9.32. Found: C, 51.37, H,6.49, N, 9.34.

EXAMPLE 125

IR (KBr): 3355, 2937, 1673, 1631, 1535, 1515, 1442, 1259, 1201, 1180,1133, 1087, 1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.3-1.6 (9H, m), 1.6-2.7 (17H, m), 3.21 (3H, s), 2.8-3.6 (12H, m),3.6-4.2 (14H, m), 4.2-4.6 (7H, m), 4.83 (3H, m), 5.0 (1H, m), 5.15 (2H,m), 5.30 (2H, m), 6.70 (1H, d, J=8.2 Hz), 6.78 (1H, d, J=8.2 Hz), 7.05(1H, s), 7.14 (2H, d, J=8.8 Hz), 7.46 (1H, d, J=8.4 Hz), 7.57 (1H, d,J=8.4 Hz), 7.88 (1H, m), 7.97 (2H, d, J=8.8 Hz), 8.05 (2H, d, J=8.5 Hz),8.12 (2H, d, J=8.5 Hz), 8.42 (1H, m), 8.7 (1H, m), 8.93 (1H, d, J=8.4Hz).

MASS (m/z): 1408.94 (M⁺−Na).

Elemental Analysis Calcd. for C₆₆H₉₃N₁₁O₂₁S₂.2TFA.5H₂O: C, 47.80, H,6.02, N, 8.76. Found: C, 47.80, H, 6.27, N, 8.90.

EXAMPLE 126

MASS (m/z): 1612.5 (M⁻−1)+1.

EXAMPLE 127

IR (KBr): 3353.6, 1664.3, 1627.6, 1446.4, 1257.4 cm⁻¹.

MASS (m/z): 1454.4 (M⁻−1).

Elemental Analysis Calcd. for C₈₆H₉₃N₁₁O₂₂S₂.7H₂O: C, 50.09, H, 6.81, N,9.73. Found: C, 49.80, H, 6.81, N, 9.73.

EXAMPLE 128

IR (KBr): 3353.6, 1658.5, 1635.3, 1517.7, 1444.4, 1255.4 cm⁻¹.

MASS (m/z): 1482.4 (M⁻−1).

Elemental Analysis Calcd. for C₆₈H₉₇N₁₁O₂₂S₂.6H₂O: C, 51.28, H, 6.90, N,9.67. Found: C, 51.57, H, 6.80, N, 9.68.

EXAMPLE 129

IR (KBr): 3401.8, 1664.3, 1635.3, 1446.4, 1255.4 cm⁻¹.

MASS (m/z): 1496.5 (M⁻−1).

EXAMPLE 130

Major Product

IR (KBr): 3351.7, 1658.5, 1635.3, 1517.7, 1444.4, 1255.4 cm⁻¹.

MASS (m/z): 1469.5 (M⁻−1)+1.

Elemental Analysis Calcd. for C₆₇H₉₅N₁₁O₂₂S₂.8H₂O: C, 49.84, H, 6.93, N,9.54. Found: C, 49.95, H, 6.52, N, 9.37.

Minor Product

IR (KBr): 3351.7, 1664.3, 1635.3, 1529.3, 1517.7, 1446.4, 1255.4 cm⁻¹.

MASS (m/z): 1439.5 (M⁻−1).

EXAMPLE 131

IR (KBr): 2935, 1649, 1539, 1514, 1452, 1257 cm⁻¹.

MASS (m/z): 1563.4 (M⁺−1).

Elemental Analysis Calcd. for C₁₂H₁₀₀N₁₂O₂₃S₂.8H₂O: C, 50.58, H, 6.84,N, 9.83. Found: C, 50.43, H, 6.69, N, 9.81.

EXAMPLE 132

MASS (m/z): 1480.4 (M⁺−1).

EXAMPLE 133

The object compound (133) was used directly in the next reaction withoutpurification.

EXAMPLE 134

The object compound (134) was used directly in the next reaction withoutpurification.

EXAMPLE 135

The object compound (135) was used directly in the next reaction withoutpurification.

EXAMPLE 136

IR (KBr): 1659, 1635, 1444, 1257 cm⁻¹.

NMR (DMSO-d₆, δ): 0.9-1.25 (6H, m), 1.25-2.6 (23H, m), 2.6-5.2 (34H, m),6.65-6.8 (2H, m), 6.98 (2H, m), 7.13 (2H, d, J=9.0 Hz), 7.2-7.8 (3H, m),7.97 (2H, d, J=8.8 Hz), 7.95-8.2 (5H, m), 8.4-8.8 (2H, m).

MASS (m/z): 1363 (M⁺+23).

Elemental Analysis Calcd. for C₅₉H₈₀N₁₂O₂₀S₂.11H₂O: C, 46.03, H, 6.68,N, 10.92. Found: C, 45.83, H, 6.26, N, 10.72.

EXAMPLE 137

IR (KBr): 1664, 1605, 1446, 1257 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.2 (6H, s), 1.2-2.7 (23H, m), 2.7-5.4 (38H, m),6.6-7.0 (2H, m), 7.14 (2H, d, J=8.8 Hz), 7.29 (1H, s), 7.51 (1H, s),7.4-7.9 (3H, m), 7.97 (2H, d, J=8.8 Hz), 8.0-8.3 (5H, m), 8.6-9.0 (2H,m).

MASS (m/z): 1391 (M⁺−1).

The following compounds [Examples 138 to 192] were obtained according toa similar manner to that of Example 1.

EXAMPLE 138

IR (KBr): 1666, 1632, 1535, 1514, 1441, 1271 cm⁻¹.

NMR (DMSO-d₆+D₂O, δ): 0.98 (3H, d, J=6.72 Hz), 1.08 (3H, d, J=5.78 Hz),1.35 (9H, s), 1.45-2.00 (6H, m), 2.10-2.40 (3H, m), 2.75-2.95 (3H, m),3.10-3.40 (2H, m), 3.60-4.50 (14H, m), 4.70-4.80 (2H, m), 6.72 (1H, d,J=8.12 Hz), 6.77 (1H, d, J=9.72 Hz), 7.02 (1H, s).

ESI MASS (m/z) (Positive): 992 (M⁺+1).

Elemental Analysis Calcd. for C₄₀H₇₄N₈O₂₅S.6H₂O: C, 43.71, H, 6.79, N,10.19. Found: C, 43.75, H, 6.71, N, 10.11.

EXAMPLE 139

IR (KBr): 3324, 2975, 2937, 1631, 1610, 1529, 1519, 1465, 1446, 1240,1176, 1085, 1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz), 1.18(6H, d, J=6.2 Hz), 1.6-2.1 (3H, m), 2.1-2.6 (6H, m), 2.98 (2H, m), 3.20(1H, m), 3.4 (2H, m), 3.73 (4H, m), 3.8-4.6 (14H, m), 4.6-5.6 (9H, m),6.70 (1H, d, J=8.2 Hz), 6.81 (1H, d, J=8.2 Hz), 6.89 (1H, s), 7.04 (1H,s), 7.11 (2H, d, J=8.9 Hz), 7.2-7.7 (4H, m), 7.78 (2H, d, J=8.9 Hz),7.95 (4H, s), 8.07 (1H, m), 8.54 (1H, m), 8.80 (1H, s), 8.95 (1H, s).

MASS (m/z): 1321.2 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₇₄N₁₂O₂₀S₂.10H₂O: C, 46.33, H, 6.30,N, 11.18. Found: C, 46.26, H, 5.98, N, 11.04.

EXAMPLE 140

IR (KBr): 3355, 2937, 1633, 1629, 1529, 1517, 1467, 1446, 1253, 1176,1114, 1083, 1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (2H, d, J=6.7 Hz), 0.96 (3H, d, J=6.7 Hz), 1.10(3H, d, J=5.7 Hz), 1.2-1.6 (8H, m), 1.6-2.1 (9H, m), 2.1-2.6 (2H, m),3.0 (3H, m), 3.40 (2H, m), 3.75 (2H, m), 3.9-4.2 (6H, m), 4.2-4.6 (7H,m), 4.6-4.9 (3H, m), 5.0 (1H, m), 5.2 (2H, m), 5.30 (1H, d, J=4.4 Hz),6.69 (1H, d, J=9.8 Hz), 6.78 (1H, d, J=9.8 Hz), 7.08 (1H, s), 7.15 (2H,d, J=9.0 Hz), 7.41 (1H, d, J=8.8 Hz), 7.5 (1H, m), 7.77 (1H, m), 7.88(2H, d, J=8.8 Hz), 7.96 (4H, s), 8.34 (1H, d, J=6.3 Hz), 8.75 (1H, d,J=8.5 Hz), 8.85 (1H, m), 8.86 (1H, s).

MASS (m/z): 1306.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₇₃N₁₁O₂₀S₂.9H₂O: C, 47.37, H, 6.24, N,10.48. Found: C, 47.32, H, 6.05, N, 10.32.

EXAMPLE 141

IR (KBr): 3328, 2937, 1635, 1529, 1519, 1465, 1444, 1255, 1178, 1112,1085, 1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz), 1.2(2H, m), 1.4-2.1 (14H, m), 2.2-2.5 (3H, m), 2.90 (3H, m), 3.22 (3H, s),3.75 (2H, m), 3.8-4.2 (9H, m), 4.2-4.6 (6H, m), 4.8 (3H, m), 5.2 (2H,m), 5.3 (1H, m), 6.70 (1H, d, J=8.2 Hz), 6.80 (1H, d, J=8.2 Hz), 7.08(1H, s), 7.15 (2H, d, J=8.8 Hz), 7.42 (1H, d, J=8.0 Hz), 7.5 (2H, m),7.77 (1H, m), 7.90 (2H, d, J=8.8 Hz), 7.96 (4H, s), 8.3 (1H, m), 8.73(1H, d, J=6.5 Hz), 8.86 (1H, s).

MASS (m/z): 1324.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₇₅N₁₁O₂₁S₂.9H₂O: C, 46.60, H, 6.30, N,10.35. Found: C, 46.66, H, 6.13, N, 10.12.

EXAMPLE 142

IR (KBr): 1651, 1539, 1514, 1234 cm⁻¹.

NMR (DMSO-d₆, δ): 0.85-1.3 (12H, m), 1.5-2.6 (10H, m), 2.7-3.6 (18H, m),3.6-5.4 (24H, m), 6.65-7.2 (9H, m), 7.3-8.0 (9H, m), 8.2-8.45 (1H, m),8.6-8.95 (2H, m).

MASS (m/z): 1358 (M⁺−1).

Elemental Analysis Calcd. for C₆₄H₈₅N₁₁O₂₀S.7H₂O: C, 51.73, H, 6.71, N,10.36. Found: C, 51.50, H, 6.70, N, 11.31.

EXAMPLE 143

IR (KBr): 2931, 1659, 1633, 1531, 1506, 1444, 1385 cm⁻¹.

NMR (DMSO-d₆, δ): 0.83 (3H, t, J=6.7 Hz), 0.96 (3H, d, J=6.8 Hz), 1.07(3H, d, J=5.4 Hz), 1.18-1.52 (10H, m), 1.60-2.08 (7H, m), 2.08-2.43 (2H,m), 2.79-3.03 (3H, m), 3.14-3.55 (2H, m), 3.65-4.54 (16H, m), 4.65-5.20(9H, m), 6.74 (1H, d, J=8.2 Hz), 6.83 (1H, d, J=8.5 Hz), 6.97 (2H, d,J=8.8 Hz), 7.08 (1H, s), 7.40 (1H, d, J=9.2 Hz), 7.33-7.86 (2H, m), 7.85(2H, d, J=8.8 Hz), 8.31 (1H, d, J=6.6 Hz), 8.58 (1H, d, J=7.8 Hz), 8.85(1H, br s).

MASS (m/z): 1137.4 (M⁺−1).

Elemental Analysis Calcd. for C₅₀O₇₄N₈O₂₀S.7H₂O: C, 47.46, H, 7.01, N,8.86. Found: C, 47.31, H, 6.85, N, 8.78.

EXAMPLE 144

IR (KBr): 3344.0, 1672.0, 1658.5, 1664.3, 1635.3, 1446.4, 1257.4 cm⁻¹.

ESI MASS (m/z): 1219 (M⁺+1).

EXAMPLE 145

IR (KBr): 2974, 2937, 1633, 1537, 1514, 1443, 1269 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.13 (3H, d, J=5.6 Hz), 1.18(3H, t, J=7.0 Hz), 1.35-2.56 (5H, m), 2.56-2.84 (46, m), 2.84-3.40 (5H,m), 3.52 (2H, q, J=7.0 Hz), 3.68-4.60 (13H, m), 4.53 (2H, s), 4.60-5.30(8H, m), 6.71 (1H, d, J=8.2 Hz), 6.77 (1H, d, J=8.2 Hz), 6.96 (1H, s),7.46 (2H, d, J=8.3 Hz), 7.77 (2H, d, J=8.2 Hz), 7.58-7.84 (2H, m), 7.92(2H, d, J=8.5 Hz), 7.84-8.27 (8H, m), 8.70-8.85 (2H, m).

MASS (m/z): 1287.3 (M⁺−1).

Elemental Analysis Calcd. for C₅₉H₇₂N₁₀O₁₉S₂.9H₂O: C, 48.82, H, 6.25, N,9.65. Found: C, 48.73, H, 6.01, N, 9.45.

EXAMPLE 146

IR (KBr): 2939, 1633, 1606, 1535, 1525, 1444, 1419, 1358 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.13 (3H, d, J=5.6 Hz),1.33-2.78 (16H, m), 2.78-5.00 (26H, m), 4.56 (2H, s), 5.00-5.35 (2H, m),6.70 (1H, d, J=8.1 Hz), 6.77 (1H, d, J=8.1 Hz), 6.96 (1H, s), 7.10 (2H,d, J=9.0 Hz), 7.20-7.80 (8H, m), 7.84 (2H, d, J=8.8 Hz), 8.06 (4H, s),8.00-8.30 (1H, m), 8.40-8.80 (2H, m).

MASS (m/z): 1342.3 (M⁺−1).

Elemental Analysis Calcd. for C₆₂H₇₇N₁₁O₁₉S₂.12H₂O: C, 47.72, H, 6.52,N, 9.87. Found: C, 47.98, H, 6.00, N, 9.72.

EXAMPLE 147

IR (KBr): 2937, 1633, 1533, 1512, 1443 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.8 Hz), 1.12 (3H, d, J=5.6 Hz),1.60-2.64 (9H, m), 2.01 (2H, t, J=6.3 Hz), 2.83-3.03 (3H, m), 3.13-3.60(2H, m), 3.27 (3H, s), 3.50 (2H, t, J=6.3 Hz), 3.68-4.58 (13H, m), 4.09(2H, t, J=6.4 Hz), 4.70-5.30 (8H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H,dd, J=8.3 and 7 Hz), 7.01 (1H, d, J=1.6 Hz), 7.08 (2H, d, J=8.8 Hz),7.45 (1H, d, J=8.4 Hz), 7.57-7.82 (2H, m), 7.73 (2H, d, J=8.8 Hz), 7.87(2H, d, J=8.5 Hz), 8.02-8.20 (6H, m), 8.30 (1H, d, J=6.2 Hz), 8.71 (1H,br s), 8.93 (1H, d, J=7.4 Hz).

MASS (m/z): 1317.3 (M⁺−1).

Elemental Analysis Calcd. for C₆₀H₇₄N₁₀O₂₀S₂.8H₂O: C, 49.24, H, 6.20, N,9.57. Found: C, 48.95, H, 6.04, N, 9.36.

EXAMPLE 148

IR (KBr): 2929, 1633, 1608, 1518, 1444, 1419 cm⁻¹.

NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6.4 Hz), 0.98 (3H, d, J=6.8 Hz),1.14-1.40 (5H, m), 1.11 (3H, d, J=5.5 Hz), 1.60-2.74 (18H, m), 1.80-3.02(3H, m), 3.02-3.58 (6H, m), 3.70-4.60 (13H, m), 4.70-5.40 (8H, m), 6.71(1H, d, J=8.2 Hz), 6.78 (1H, dd, J=8.1 and 1.6 Hz), 7.01 (1H, d, J=1.7Hz), 7.08 (2H, d, J=8.7 Hz), 7.25 (1H, d, J=8.8 Hz), 7.57-7.92 (2H, m),7.45 (2H, d, J=8.4 Hz), 8.00-8.20 (4H, m), 8.31 (1H, d, J=6.4 Hz), 8.71(1H, br s), 8.91 (1H, d, J=7.7 Hz).

MASS (m/z): 1333.4 (M⁺−1).

Elemental Analysis Calcd. for C₆₁H₈₂N₁₂O₁₈S₂.9H₂O: C, 48.92, H, 6.73, N,11.22. Found: C, 49.12, H, 6.71, N, 11.08.

EXAMPLE 149

IR (KBr): 2933, 2860, 1659, 1630, 1547, 1510, 1446, 1387, 1329 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.07 (3H, d, J=5.2 Hz),1.26-1.60 (10H, m), 1.60-2.08 (5H, m), 2.18 (6H, s), 2.12-2.67 (4H, m),2.79-3.03 (3H, m), 3.10-3.50 (12H, m), 3.21 (3H, s), 3.64 (2H, t, J=6.2Hz), 3.64-4.08 (6H, m), 4.12-4.52 (7H, m), 4.67-5.26 (8H, m), 6.65 (2H,s), 6.64-6.84 (2H, m), 6.94-7.10 (3H, m), 7.43 (1H, d, J=8.8 Hz),7.34-7.97 (2H, m), 7.80 (2H, d, J=8.7 Hz), 8.22-8.40 (1H, m), 8.40-8.59(1H, m), 8.72 (1H, br s).

MASS (m/z): 1325.6 (M⁺−1).

Elemental Analysis Calcd. for C₆₂H₉₀N₁₀O₂₀S.6H₂O: C, 51.87, H, 7.16, N,9.76. Found: C, 51.80, H, 7.15, N, 9.72.

EXAMPLE 150

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.9 Hz), 1.07 (3H, d, J=5.2 Hz),0.80-2.67 (21H, m), 2.77-3.00 (3H, m), 3.08-2.58 (10H, m), 3.52 (2H, t,J=6.3 Hz), 3.68-4.51 (16H, m), 4.70-5.28 (8H, m), 6.68-7.10 (9H, m),7.43 (1H, d, J=8.8 Hz), 7.56-7.90 (2H, m), 7.80 (2H, d, J=8.8 Hz),8.26-8.40 (1H, m), 8.40-8.55 (1H, m), 8.65-8.80 (1H, m).

MASS (m/z): 1309.5 (M⁺−1).

EXAMPLE 151

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.10 (3H, d, J=6.0 Hz), 1.39(9H, s), 1.65-2.83 (22H, m), 1.81-3.06 (3H, m), 3.20-4.54 (18H, m),4.69-5.34 (8H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H, dd, J=8.3 and 1.8Hz), 6.70-6.90 (1H, m), 6.98-7.14 (3H, m), 7.44 (1H, d, J=8.8 Hz), 7.68(2H, d, J=8.7 Hz), 7.72 (2H, d, J=8.3 Hz), 7.38-7.86 (2H, m), 7.95 (2H,d, J=8.5 Hz), 8.33 (1H, d, J=6.8 Hz), 8.70 (1H, br s), 8.75 (1H, d,J=7.7 Hz).

MASS (m/z): 1324.5 (M⁺−1).

EXAMPLE 152

IR (KBr): 1632, 1514, 1452, 1234 cm⁻¹.

NMR (DMSO-d₆, δ): 0.9-1.3 (12H, m), 1.5-2.6 (11H, m), 2.7-3.6 (18H, m),3.6-5.3 (23H, m), 6.7-7.2 (9H, m), 7.4-7.55 (1H, m), 7.6-7.85 (7H, m),7.94 (2H, d, J=8.3 Hz), 8.2-8.4 (1H, m), 8.65-8.8 (1H, m).

MASS (m/z): 1266 (M⁺+23).

Elemental Analysis Calcd. for C₆₄H₈₅N₁₁O₁₉S.7H₂O: C, 52.27, H, 6.79, N,10.48. Found: C, 52.00, H, 6.61, N, 10.42.

EXAMPLE 153

NMR (DMSO-d₆, δ): 0.8-1.3 (6H, m), 1.4-2.6 (13H, m), 2.6-3.6 (15H, m),3.7-5.3 (21H, m), 6.65-6.9 (2H, m), 6.96 (1H, s), 7.15 (2H, d, J=8.3Hz), 7.35-7.8 (7H, m), 7.86 (2H, d, J=8.7 Hz), 7.9-8.2 (5H, m), 8.6-8.9(2H, m).

MASS (m/z): 1376 (M⁺−23).

EXAMPLE 154

IR (KBr): 3380.6, 1645.0, 1631.5, 1608.3, 1538.9, 1515.8, 1442.5,1419.4, 1268.9, 1240.0 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.8 Hz), 1.11 (3H, d, J=5.6 Hz),1.2-5.4 (48H, m), 6.71 (1H, d, J=8.2 Hz), 6.7-6.9 (1H, m), 7.01 (1H, d,J=1.8 Hz), 7.07 (2H, d, J=9.1 Hz), 7.45 (1H, d, J=9.2 Hz), 7.5-7.9 (2H,m), 7.83 (2H, d, J=8.9 Hz), 8.07 (4H, s), 8.30 (1H, d, J=5.9 Hz),8.5-8.8 (1H, m), 8.90 (1H, d, J=7.8 Hz).

MASS (m/z): 1236.3 (M⁻−1).

Elemental Analysis Calcd. for C₅₅H₇₁N₁₁O₁₈S₂.10H₂O: C, 46.57, H, 6.47,N, 10.86. Found: C, 46.74, H, 6.12, N, 10.75.

EXAMPLE 155

IR (KBr): 3359.4, 1645.0, 1631.5, 1538.9, 1515.8, 1438.6, 1255.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.91 (3H, t, J=7.1 Hz), 0.97 (3H, d, J=6.8 Hz), 1.10(3H, d, J=5.8 Hz), 1.2-5.4 (46H, m), 6.71 (1H, d, J=8.1 Hz), 6.7-6.9(1H, m), 7.00 (1H, d, J=1.6 Hz), 7.08 (2H, d, J=8.9 Hz), 7.45 (1H, d,J=8.3 Hz), 7.5-8.1 (3H, m), 7.80 (2H, d, J=8.4 Hz), 7.91 (2H, d, J=8.8Hz), 7.98 (2H, d, J=8.5 Hz), 8.2 (1H, m), 8.39 (1H, s), 8.79 (1H, d,J=7.9 Hz).

MASS (m/z): 1238.3 (M⁻−1).

Elemental Analysis Calcd. for C₅₆H₇₃N₉O₁₉S₂.9H₂O: C, 47.96, H, 6.54, N,8.99. Found: C, 48.14, H, 6.36, N, 8.90.

EXAMPLE 156

IR (KBr): 3355.5, 1635.3, 1529.3, 1517.7, 1434.8, 1255.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.87 (3H, t, J=6.5 Hz), 0.97 (3H, d, J=6.8 Hz), 1.11(3H, d, J=5.8 Hz), 1.2-5.4 (52H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H,d, J=9.9 Hz), 7.00 (1H, d, J=1.6 Hz), 7.09 (2H, d, J=9.0 Hz), 7.45 (1H,d, J=8.8 Hz), 7.5-7.9 (2H, m), 7.97 (2H, d, J=8.5 Hz), 8.06 (2H, d,J=8.5 Hz), 8.29 (1H, d, J=8.9 Hz), 8.40 (2H, d, J=8.8 Hz), 8.81 (1H, d,J=7.4 Hz), 9.26 (2H, s).

MASS (m/z): 1275.4 (M⁻−1).

Elemental Analysis Calcd. for C₆₀H₈₀N₁₀O₁₉S.8H₂O: C, 50.70, H, 6.81, N,9.85. Found: C, 50.50, H, 6.69, N, 9.69.

EXAMPLE 157

IR (KBr): 3361.3, 1631.5, 1511.9, 1446.4, 1267.0, 1232.3, 1045.2 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.8 Hz),1.0-5.6 (57H, m), 6.70 (1H, d, J=8.1 Hz), 6.7-6.9 (1H, m), 6.92 (2H, d,J=8.7 Hz), 6.99 (1H, s), 7.01 (2H, d, J=9.4 Hz) 7.09 (2H, d, J=8.7 Hz),7.3-7.9 (3H, m), 7.80 (2H, d, J=8.8 Hz), 8.1-8.5 (3H, m).

MASS (m/z): 1235.4 (M⁻−H).

Elemental Analysis Calcd. for C₅₈H₈₀N₁₀O₁₈S.9H₂O: C, 49.78, H, 7.06, N,10.01. Found: C, 49.88, H, 6.87, N, 9.89.

EXAMPLE 158

IR (KBr): 3359.4, 1633.4, 1535.1, 1511.9, 1442.5, 1251.6 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.1 (6H, m), 1.1-1.3 (3H, m), 1.3-5.6 (42H, m),6.71 (1H, d, J=8.1 Hz), 6.77 (1H, d, J=9.8 Hz), 6.97 (1H, s), 7.07 (2H,d, J=8.9 Hz), 7.2-9.0 (15H, m).

MASS (m/z): 1287.4 (M⁻−1).

EXAMPLE 159

IR (KBr): 3359.4, 1631.5, 1610.3, 1538.9, 1502.3, 1450.2, 1230.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.0-1.3 (3H, m), 1.3-5.8 (59H,m), 6.70 (1H, d, J=8.2 Hz), 6.77 (1H, d, J=9.9 Hz), 6.8-7.3 (8H, m),7.3-9.2 (11H, m).

MASS (m/z): 1345.5 (M⁻−1).

EXAMPLE 160

MASS (m/z): 1222.3 (M⁻−1).

EXAMPLE 161

IR (KBr): 3353.6, 1631.5, 1537.0, 1517.7, 1467.6, 1440.6, 1272.8, 1045.2cm⁻¹.

NMR (DMSO-d₆, δ): 0.7-1.0 (3H, m), 0.98 (3H, d, J=6.8 Hz), 1.11 (3H, d,J=5.6 Hz), 1.2-5.5 (46H, m), 6.71 (1H, d, J=8.1 Hz), 6.7-6.9 (1H, m),7.00 (1H, d, J=1.6 Hz), 7.45 (1H, d, J=8.1 Hz), 7.5-8.2 (13H, m), 8.30(1H, d, J=7.6 Hz), 8.77 (1H, d, J=7.1 Hz).

MASS (m/z): 1256.4 (M⁻−1).

Elemental Analysis Calcd. for C₆₀H₇₅N₉O₁₉S.8H₂O: C, 51.38, H, 6.54, N,8.99. Found: C, 51.15, H, 6.41, N, 8.76.

EXAMPLE 162

IR (KBr): 3425.0, 3396.0, 3365.2, 1631.5, 1537.0, 1510.0, 1450.2,1286.3, 1267.0, 1234.2 cm⁻¹.

NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.3-5.6 (63H, m), 6.7-7.2 (9H, m), 7.3-7.8 (3H, m), 7.80 (2H, d, J=8.8Hz), 8.0-8.5 (2H, m).

MASS (m/z): 1313.4 (M⁻−1).

Elemental Analysis Calcd. for C₆₀H₈₆N₁₀O₂₁S.10H₂O: C, 48.19, H, 7.14, N,9.37. Found: C, 48.45, H, 6.94, N, 9.32.

EXAMPLE 163

IR (KBr): 1469, 1541, 1514 cm⁻¹.

NMR (DMSO-d₆, δ): 0.7-1.6 (11H, m), 1.6-2.7 (15H, m), 2.7-3.6 (8H, m),3.6-5.3 (21H, m), 6.7-6.9 (2H, m), 7.00 (1H, s), 7.2-7.9 (5H, m), 7.96(2H, d, J=8.3 Hz), 8.0-8.4 (5H, m), 8.6-9.0 (2H, m).

MASS (m/z): 1235 (M⁺−1).

Elemental Analysis Calcd. for C₅₆H₇₂N₁₀O₁₈S₂.7H₂O: C, 49.33, H, 6.36, N,10.27. Found: C, 49.07, H, 6.40, N, 10.02.

EXAMPLE 164

IR (KBr): 1633, 1516, 1444, 1255 cm⁻¹.

NMR (DMSO-d₆, δ): 0.9-2.6 (25H, m), 2.7-3.6 (8H, m), 3.6-5.3 (22H, m),6.65-6.85 (2H, m), 7.00 (1H, s), 7.14 (2H, d, J=9.0 Hz), 7.4-8.2 (10H,m), 8.2-8.4 (1H, m), 8.8-9.0 (1H, m).

MASS (m/z): 1251 (M⁺−1).

Elemental Analysis Calcd. for C₅₆H₇₂N₁₀O₁₉S₂.8H₂O: C, 48.13, H, 6.35, N,10.02. Found: C, 48.26, H, 6.35, N, 9.80.

EXAMPLE 165

IR (KBr): 1633, 1518, 1444, 1250 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.6 (15H, m), 1.6-2.6 (11H, m), 2.7-3.6 (8H, m),3.6-5.3 (23H, m), 6.65-6.85 (2H, m), 7.00 (1H, s), 7.10 (2H, d, J=9.0Hz), 7.3-8.4 (12H, m), 8.8-9.0 (1H, m), 9.23 (1H, s).

MASS (m/z): 1365 (M⁺+23).

Elemental Analysis Calcd. for C₅₉H₇₆N₁₂O₁₉S₂.9H₂O: C, 47.77, H, 6.39, N,11.33. Found: C, 47.67, H, 6.19, N, 11.20.

EXAMPLE 166

IR (KBr): 1662, 1635, 1605, 1444 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.4 (6H, m), 1.5-2.6 (13H, m), 2.6-3.6 (1H, m),3.6-5.3 (23H, m), 6.65-6.85 (2H, m), 6.99 (1H, s), 7.05-8.4 (18H, m),8.8-9.0 (1H, m).

MASS (m/z): 1312 (M⁺−1).

Elemental Analysis Calcd. for C₆₁H₇₅N₁₁O₁₈S₂.9H₂O: C, 49.62, H, 6.35, N,10.43. Found: C, 49.73, H, 6.16, N, 10.27.

EXAMPLE 167

IR (KBr): 1659, 1628, 1605, 1444 cm⁻¹.

NMR (DMSO-d₆, δ): 0.9-2.7 (29H, m), 2.7-5.3 (35H, m), 6.65-6.85 (2H, m),6.9-7.2 (3H, m), 7.3-7.95 (5H, m), 8.0-8.4 (6H, m), 8.8-9.0 (1H, m).

MASS (m/z): 1334 (M⁺−1).

Elemental Analysis Calcd. for C₆₁H₈₁N₁₁O₁₉S₂.9H₂O: C, 48.89, H, 6.66, N,10.28. Found: C, 48.83, H, 6.45, N, 10.11.

EXAMPLE 168

IR (KBr): 1659, 1628, 1444 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-2.7 (34H, m), 3.8-3.6 (8H, m), 3.6-5.3 (23H, m),6.65-6.85 (2H, m), 6.99 (1H, s), 7.3-7.85 (5H, m), 7.9-8.4 (7H, m), 8.57(1H, s), 8.6-9.0 (1H, m).

MASS (m/z): 1283 (M⁺−1).

Elemental Analysis Calcd. for C₅₇H₈₀N₁₂O₁₈S₂.8H₂O: C, 47.89, H, 6.77, N,11.76. Found: C, 47.65, H, 6.63, N, 11.53.

EXAMPLE 169

IR (KBr): 3324, 2937, 1658, 1629, 1529, 1517, 1465, 1446, 1255, 1178,1112, 1085, 1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.3-1.6 (4H, m), 1.6-2.1 (4H, m), 2.1-2.5 (3H, m), 2.9 (3H, m), 3.23(1H, s), 3.38 (2H, m), 3.7-4.6 (19H, m), 4.8 (4H, m), 5.2 (3H, m), 6.71(1H, d, J=8.2 Hz), 6.78 (1H, d, J=8.2 Hz), 7.00 (18H, s), 7.15 (2H, d,J=8.8 Hz), 7.44 (1H, d, J=8.5 Hz), 7.6-7.8 (3H, m), 7.67 (1H, m), 7.90(2H, d, J=8.8 Hz), 7.97 (4H, s), 8.34 (1H, d, J=7.1 Hz), 8.75 (1H, d,J=7.5 Hz), 8.86 (1H, s).

MASS (m/z): 1308.3 (M⁺+1).

Elemental Analysis Calcd. for C₅₈H₇₅N₁₁O₂₀S₂.8H₂O: C, 47.89, H, 6.31, N,10.59. Found: C, 48.02, H, 6.21, N, 10.49.

EXAMPLE 170

IR (KBr): 3300, 1635.3, 1510.0, 1232.3 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.8 Hz), 1.07 (3H, d, J=5.3 Hz),1.72-5.21 (58H, m), 6.69-8.67 (20H, m).

MASS (m/z): 1377.4 (M⁺+Na).

Elemental Analysis Calcd. for C₆₄H₈₄ClN₁₁O₁₉S.6H₂O: C, 51.69, H, 6.51,N, 10.36. Found: C, 51.74, H, 6.54, N, 10.59.

EXAMPLE 171

IR (KBr): 3347.8, 1631.5, 1610.3, 1510.0, 1230.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.9 Hz), 1.08 (3H, d, J=4.6 Hz),1.70-5.40 (55H, m), 6.67-8.71 (22H, m).

MASS (m/z): 1313.4.

Elemental Analysis Calcd. for C₆₃H₈₃N₁₁O₁₈S.4H₂O: C, 54.57, H, 6.61, N,11.11. Found: C, 54.32, H, 6.64, N, 11.00.

EXAMPLE 172

IR (KBr): 1659, 1635, 1606, 1529, 1446, 1242 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.3 (12H, m), 1.4-2.6 (11H, m), 2.7-3.6 (8H, m),3.6-5.3 (25H, m), 6.1-6.85 (2H, m), 6.99 (1H, s), 7.11 (2H, d, J=8.7Hz), 7.4-7.85 (3H, m), 7.87 (2H, d, J=8.9 Hz), 8.0-8.4 (6H, m), 8.8 (1H,m).

MASS (m/z): 1266 (M⁺−1).

Elemental Analysis Calcd. for C₅₆H₇₃N₁₁O₁₉S₂.10H₂O: C, 46.43, H, 6.47,N, 10.64. Found: C, 46.45, H, 5.95, N, 10.46.

EXAMPLE 173

IR (KBr): 1659, 1635, 1612, 1512, 1446, 1234 cm⁻¹.

NMR (DMSO-d₆, δ): 0.9-1.3 (12H, m), 1.5-2.4 (11H, m), 2.7-3.6 (18H, m),3.6-5.3 (23H, m), 6.6-7.1 (9H, m), 7.3-7.9 (6H, m), 8.2-8.5 (2H, m).

MASS (m/z): 1266 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₈₁N₁₁O₁₉S.7H₂O: C, 49.96, H, 6.87, N,11.05. Found: C, 49.78, H, 6.64, N, 10.93.

EXAMPLE 174

IR (KBr): 1659, 1628, 1510, 1446, 1236 cm⁻¹.

NMR (DMSO-d₆, δ): 0.7-1.5 (22H, m), 1.5-2.6 (16H, m), 2.7-3.6 (12H, m),3.6-5.3 (21H, m), 6.6-7.05 (5H, m), 7.3-7.9 (6H, m), 8.2-8.5 (2H, m).

MASS (m/z): 1215 (M⁺−1).

Elemental Analysis Calcd. for C₅₆H₈₄N₁₀O₁₈S.7H₂O: C, 50.06, H, 7.35, N,10.43. Found: C, 49.95, H, 7.19, N, 10.30.

EXAMPLE 175

IR (KBr): 1630, 1510, 1446, 1238 cm⁻¹.

NMR (DMSO-d₆, δ): 0.7-1.4 (20H, m), 1.6-2.75 (18H, m), 2.75-3.7 (12H,m), 3.7-4.55 (13H, m), 4.6-5.3 (8H, m), 6.6-7.1 (5H, m), 7.3-7.9 (5H,m), 8.2-8.6 (2H, m), 8.71 (1H, s).

MASS (m/z): 1215 (M⁺−1).

Elemental Analysis Calcd. for C₅₆H₈₄N₁₀O₁₈S.8H₂O: C, 49.40, H, 7.40, N,10.29. Found: C, 49.45, H, 7.28, N, 10.20.

EXAMPLE 176

IR (KBr): 1664, 1635, 1446, 1240 cm⁻¹.

NMR (DMSO-d₆, δ): 0.7-1.3 (6H, m), 1.4-2.65 (15H, m), 2.7-3.6 (12H, m),3.65-5.3 (21H, m), 6.65-6.85 (2H, m), 6.9-7.2 (3H, m), 7.3-7.85 (5H, m),7.9-8.4 (7H, m), 8.7-8.95 (1H, m), 9.17 (1H, s).

MASS (m/z): 1303 (M⁺).

Elemental Analysis Calcd. for C₅₈H₇₃N₁₃O₁₈S.7H₂O: C, 48.70, H, 6.13, N,12.73. Found: C, 48.48, H, 5.79, N, 12.45.

EXAMPLE 177

IR (KBr): 1649, 1632, 1539, 1512, 1454, 1238 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-2.75 (39H, m), 2.75-5.3 (36H, m), 6.65-7.05 (5H,m), 7.3-7.9 (5H, m), 8.2-8.6 (2H, m), 8.71 (1H, s).

MASS (m/z): 1271 (M⁺−1).

Elemental Analysis Calcd. for C₅₉H₈₈N₁₀O₁₉S.7H₂O: C, 49.99, H, 7.39, N,9.88. Found: C, 49.80, H, 7.21, N, 10.11.

EXAMPLE 178

IR (KBr): 1651, 1541, 1512, 1232 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.2 (9H, m), 1.4-2.1 (12H, m), 2.1-3.6 (26H, m),3.6-4.5 (13H, m), 4.6-5.3 (8H, m), 6.6-7.1 (9H, m), 7.3-7.9 (5H, m),8.2-8.8 (3H, m).

MASS (m/z): 1310 (M⁺−1).

Elemental Analysis Calcd. for C₅₆H₈₄N₁₀O₁₈S.7H₂O: C, 50.09, H, 6.94, N,10.71. Found: C, 49.86, H, 6.80, N, 10.65.

EXAMPLE 179

IR (KBr): 1649, 1632, 1539, 1512, 1454, 1238 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-2.7 (39H, m), 2.7-5.3 (36H, m), 6.65-7.1 (5H, m),7.3-7.8 (5H, m), 8.25-8.55 (2H, m), 8.70 (1H, s).

MASS (m/z): 1273 (M⁺+1).

Elemental Analysis Calcd. for C₅₉H₈₈N₁₀O₁₉S.7H₂O: C, 50.63, H, 7.35, N,10.01. Found: C, 50.54, H, 7.24, N, 9.87.

EXAMPLE 180

IR (KBr): 1649, 1632, 1541, 1506, 1454, 1232 cm⁻¹.

NMR (DMSO-d₆, δ): 0.9-1.3 (12H, m), 1.6-2.6 (11H, m), 2.6-5.3 (41H, m),6.7-7.2 (9H, m), 7.3-7.9 (10H, m), 8.2-8.6 (2H, m).

MASS (m/z): 1342 (M⁺−1).

Elemental Analysis Calcd. for C₆₄H₈₅N₁₁O₁₉S.10H₂O: C, 50.42, H, 6.94, N,10.11. Found: C, 50.71, H, 6.82, N, 10.03.

EXAMPLE 181

IR (KBr): 3353.6, 1633.4, 1537.0, 1508.1, 1438.6, 1257.4, 1045.2 cm⁻¹.

NMR (DMSO-d₆, δ): 0.91 (3H, t, J=7.1 Hz), 0.98 (3H, d, J=6.8 Hz), 1.11(3H, d, J=5.8 Hz), 1.2-5.6 (45H, m), 6.71 (1H, d, J=8.1 Hz), 6.78 (1H,d, J=10.0 Hz), 7.00 (11H, s), 7.13 (2H, d, J=8.9 Hz), 7.45 (1H, d, J=8.8Hz), 7.54 (1H, s), 7.6-8.0 (2H, m), 7.85 (2H, d, J=8.7 Hz), 7.99 (2H, d,J=8.8 Hz), 8.05 (2H, d, J=8.6 Hz), 8.31 (1H, d, J=7.1 Hz), 8.71 (1H, s),8.87 (1H, d, J=7.1 Hz).

MASS (m/z): 1222.3 (M⁻−1).

Elemental Analysis Calcd. for C₅₆H₇₃N₉O₂₀S.7H₂O: C, 49.81, H, 6.49, N,9.33. Found: C, 49.99, H, 6.43, N, 9.30.

EXAMPLE 182

IR (KBr): 3374.6, 1658.5, 1627.6, 1529.3, 1517.7, 1486.8, 1446.4,1276.6, 1247.7 cm⁻¹.

NMR (DMSO-d₆, δ): 0.91 (3H, t, J=7.1 Hz), 0.97 (3H, d, J=6.9 Hz), 1.12(3H, d, J=5.8 Hz), 1.2-6.5 (46H, m), 6.71 (1H, d, J=8.1 Hz), 6.77 (1H,d, J=10.0 Hz), 6.99 (1H, d, J=1.6 Hz), 7.20 (2H, d, J=8.9 Hz), 7.46 (1H,d, J=9.5 Hz), 7.5-8.3 (3H, m), 8.08 (2H, d, J=8.6 Hz), 8.14 (2H, d,J=8.8 Hz), 8.17 (2H, d, J=8.4 Hz), 8.3-8.8 (1H, m), 8.84 (1H, d, J=7.2Hz).

MASS (m/z): 1231.3 (M⁻−1).

Elemental Analysis Calcd. for C₅₉H₇₂N₉NaO₂₀S.7H₂O: C, 49.81, H, 6.49, N,9.33. Found: C, 49.99, H, 6.43, N, 9.30.

EXAMPLE 183

IR (KBr): 3353.6, 1633.4, 1538.9, 1502.3, 1461.8, 1444.4, 1259.3, 1045.2cm⁻¹.

NMR (DMSO-d₆, δ): 0.91 (3H, t, J=7.1 Hz), 0.97 (3H, d, J=7.0 Hz), 1.11(3H, d, J=5.7 Hz), 1.2-6.5 (45H, m), 6.71 (1H, d, J=8.2 Hz), 6.7-6.9(1H, m), 6.99 (1H, d, J=1.7 Hz), 7.04 (2H, d, J=8.8 Hz), 7.45 (1H, d,J=9.0 Hz), 7.5-7.9 (10H, m), 8.00 (2H, d, J=8.4 Hz), 8.26 (1H, d, J=7.1Hz), 8.3-8.7 (1H, m), 8.73 (1H, d, J=7.9 Hz).

MASS (m/z): 1223.3 (M⁻−1).

Elemental Analysis Calcd. for C₅₉H₇₆N₈O₁₉S.6H₂O: C, 52.83, H, 6.61, N,8.35. Found: C, 59.91, H, 6.54, N, 8.32.

EXAMPLE 184

IR (KBr): 3353.6, 1658.5, 1633.4, 1232.3 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.7 Hz),1.50-5.30 (56H, m), 6.68-8.40 (23H, m).

MASS (m/z): 1342.3 (M⁺−1).

Elemental Analysis Calcd. for C₆₄H₈₅N₁₁O₁₉S.7H₂O: C, 52.27, H, 6.79, N,10.48. Found: C, 51.98, H, 6.47, N, 10.59.

EXAMPLE 185

IR (KBr): 3347.8, 1633.4, 1511.9, 1230.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.07 (3H, d, J=5.0 Hz),1.20-5.22 (66H, m), 6.64-8.56 (17H, m).

MASS (m/z): 1334.5 (M⁺+1).

Elemental Analysis Calcd. for C₆₃H₈₉N₁₁O₁₉S.7H₂O: C, 51.74, H, 7.10, N,10.53. Found: C, 52.06, H, 6.95, N, 10.49.

EXAMPLE 186

IR (KBr): 3365.2, 1664.3, 1633.4, 1230.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.81-5.25 (78H, m), 6.67-8.53 (14H, m).

Elemental Analysis Calcd. for C₆₁H₉₂N₁₀O₁₉S.12H₂O: C, 48.28, H, 7.70, N,9.23. Found: C, 48.02, H, 6.69, N, 9.39.

EXAMPLE 187

IR (KBr): 3350. 1631.5, 1511.9, 1232.3 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.6 Hz), 1.09 (3H, d, J=6.0 Hz),1.42-5.20 (61H, m), 6.68-8.40 (18H, m).

MASS (m/z): 1292.3 (M⁺+1).

Elemental Analysis Calcd. for C₆₁H₈₅N₁₀O₁₈S.7H₂O: C, 51.65, H, 7.03, N,10.86. Found: C, 51.72, H, 6.86, N, 10.86.

EXAMPLE 188

IR (KBr): 1658.5, 1629.6, 1511.9, 1232.3 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.5 Hz), 1.11 (3H, d, J=5.1 Hz),1.51-5.19 (58H, m), 6.68-8.29 (17H, m).

MASS (m/z): 1294.4 (M⁺−1).

Elemental Analysis Calcd. for C₅₉H₈₁N₁₁O₂₀S.7H₂O: C, 49.82, H, 6.73, N,10.83. Found: C, 50.33, H, 6.42, N, 11.00.

EXAMPLE 189

IR (KBr): 3328, 2940, 1664, 1629, 1529, 1519, 1467, 1446, 1257, 1178,1112, 1085, 1047 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.5-2.1 (11H, m), 2.2-2.5 (5H, m), 2.90 (3H, m), 3.24 (3H, s), 3.38 (2H,m), 3.4 (2H, m), 3.6-4.6 (18H, m), 4.6-4.9 (3H, m), 5.20 (2H, m), 6.70(1H, d, J=8.2 Hz), 6.80 (1H, d, J=8.2 Hz), 7.00 (1H, s), 7.15 (2H, d,J=8.8 Hz), 7.45 (1H, d, J=8.0 Hz), 7.7 (3H, m), 7.90 (2H, d, J=8.8 Hz),7.96 (4H, s), 8.3 (1H, m), 8.70 (1H, d, J=7.8 Hz), 8.85 (1H, s).

MASS (m/z): 1294.3 (M⁺−1).

EXAMPLE 190

IR (KBr): 3324, 2937, 1658, 1635, 1529, 1517, 1465, 1446, 1257, 1178,1114, 1087, 1045 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.2-1.6 (6H, m), 1.6-2.1 (4H, m), 2.1-2.5 (3H, m), 2.9 (3H, m), 3.22(3H, s), 3.38 (2H, m), 3.6-4.3 (14H, m), 4.3-4.6 (5H, m), 4.6-4.9 (4H,m), 5.2 (3H, m), 6.70 (1H, d, J=8.2 Hz), 6.78 (1H, d, J=8.2 Hz), 7.00(1H, s), 7.14 (2H, d, J=8.8 Hz), 7.44 (1H, d, J=8.2 Hz), 7.6-7.8 (3H,m), 7.90 (2H, d, J=8.8 Hz), 7.96 (4H, s), 8.33 (1H, d, J=7.1 Hz), 8.74(1H, d, J=7.7 Hz), 8.86 (1H, s).

MASS (m/z): 1322.4 (M⁺−1).

EXAMPLE 191

IR (KBr): 2937, 2864, 1659, 1632, 1510, 1446, 1387, 1327 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.08 (3H, d, J=5.8 Hz),1.22-2.60 (17H, m), 2.79-3.03 (3H, m), 3.10-3.55 (12H, m), 3.21 (3H, s),3.64-4.08 (6H, m), 3.85 (2H, t, J=6.5 Hz), 4.12-4.52 (7H, m), 4.67-4.90(6H, m), 5.10-5.25 (2H, m), 6.65-7.08 (9H, m), 7.43 (1H, d, J=8.2 Hz),7.53-7.88 (2H, m), 7.80 (2H, d, J=8.8 Hz), 8.27 (2H, d, J=7.8 Hz), 8.44(1H, d, J=7.6 Hz).

MASS (m/z): 1283.4 (M⁺−1).

Elemental Analysis Calcd. for C₅₉H₈₄N₁₀O₂₀S.5H₂O: C, 51.52, H, 6.89, N,10.18. Found: C, 51.51, H, 6,96, N, 10.09.

EXAMPLE 192

IR (KBr): 2935, 2856, 1633, 1533, 1518, 1497, 1446, 1385 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.4 Hz),1.05-1.38 (6H, m), 1.50-2.14 (9H, m), 2.14-2.43 (2H, m), 2.43-2.67 (7H,m), 2.79-3.03 (3H, m), 3.10-3.50 (6H, m), 3.64-4.08 (6H, m), 4.12-4.52(7H, m), 4.67-5.26 (8H, m), 6.67-6.84 (2H, m), 6.96-7.10 (1H, m), 7.02(2H, d, J=8.8 Hz), 7.44 (1H, d, J=8.9 Hz), 7.61 (2H, d, J=8.8 Hz),7.52-7.50 (2H, m), 7.70 (2H, d, J=8.2 Hz), 7.93 (2H, d, J=8.4 Hz),8.26-8.40 (1H, m), 8.68-8.84 (2H, m).

MASS (m/z): 1235.4 (M⁺−1).

Elemental Analysis Calcd. for C₅₈H₈₀N₁₀O₁₈S.7H₂O: C, 51.09, H, 6.95, N,10.27. Found: C, 50.78, H, 6.88, N, 10.10.

EXAMPLE 193

To a solution of the starting compound (193) (21 mg) in methanol (1 ml)was added a solution of hydrogen chloride in methanol (0.5 ml), andstirred for 4 hours at ambient temperature. The reaction mixture wasdiluted with water, and subjected to column chromatography on ODS(YMC-gel ODS-AM-S-50 (Trademark: prepared by Yamamura Chemical Lab.))eluting with 20% acetonitrile aqueous solution. The fractions containingthe object compound were combined, and evaporated under reduced pressureto remove acetonitrile. The residue was lyophilized to give the objectcompound (193) (19 mg).

IR (KBr): 3355, 2935, 1658, 1635, 1529, 1446, 1255, 1180, 1083, 1006cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.7 Hz), 1.04 (3H, d, J=5.7 Hz),1.2-1.6 (8H, m), 1.6-2.6 (13H, m), 2.6-3.8 (5H, m), 3.10 (9H, s), 3.21(3H, s), 3.30 (4H, t, J=6.4 Hz), 3.8-4.7 (12H, m), 4.7-5.0 (3H, m), 5.2(3H, m), 5.74 (1H, m), 6.38 (1H, d, J=8.2 Hz), 6.59 (1H, s), 6.60 (1H,d, J=8.2 Hz), 7.14 (2H, d, J=8.8 Hz), 7.37 (1H, d, J=9.2 Hz), 7.53 (1H,d, J=9.2 Hz), 7.84 (1H, m), 7.97 (2H, d, J=8.8 Hz), 8.06 (2H, d, J=8.8Hz), 8.11 (2H, d, J=8.8 Hz), 8.67 (2H, d, J=4.0 Hz), 8.85 (1H, d, J=8.2Hz), 8.91 (1H, d, J=8.2 Hz).

MASS (m/z): 1261.5 (M⁺).

The following compounds [Examples 194 to 206] were obtained according toa similar manner to that of Example 193.

EXAMPLE 194

IR (KBr): 3353, 2937, 1664, 1627, 1606, 1529, 1446, 1255, 1178, 1112,1087, 1066, 1006 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.7 Hz),1.2-1.6 (12H, m), 1.6-3.8 (23H, m), 3.21 (3H, s), 3.28 (4H, t, J=6.4Hz), 3.8-4.25 (9H, m), 4.25-4.6 (4H, m), 4.8 (4H, m), 5.1 (1H, m), 5.18(1H, d, J=3.0 Hz), 5.23 (1H, d, J=5.6 Hz), 5.40 (1H, m), 6.39 (1H, d,J=8.0 Hz), 6.57 (1H, m), 6.61 (1H, d, J=8.0 Hz), 7.14 (2H, d, J=8.8 Hz),7.42 (1H, d, J=8.8 Hz), 7.55 (1H, m), 7.80 (1H, m), 7.97 (2H, d, J=8.8Hz), 8.07 (2H, d, J=8.8 Hz), 8.12 (2H, d, J=8.8 Hz), 8.57 (1H, d, J=7.8Hz), 8.68 (2H, s), 8.89 (1H, d, J=7.3 Hz).

MASS (m/z): 1290.4 (M⁺+1).

EXAMPLE 195

IR (KBr): 3353, 2935, 1658, 1635, 1606, 1529, 1446, 1255, 1180, 1114,1085, 1062, 1004 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.08 (3H, d, J=5.7 Hz),1.2-1.6 (10H, m), 1.6-2.6 (21H, m), 2.6-3.8 (7H, m), 3.21 (3H, s), 3.30(4H, t, J=6.4 Hz), 3.8-4.5 (11H, m), 4.8 (3H, m), 5.05 (1H, m), 5.2-5.3(2H, m), 5.38 (1H, m), 6.39 (1H, d, J=8.0 Hz), 6.57 (1H, m), 6.60 (1H,d, J=8.0 Hz), 7.14 (2H, d, J=8.8 Hz), 7.41 (1H, d, J=8.7 Hz), 7.45 (1H,d, J=8.7 Hz), 7.87 (1H, d, J=6.8 Hz), 7.97 (2H, d, J=8.8 Hz), 8.06 (2H,d, J=8.8 Hz), 8.12 (21H, d, J=8.8 Hz), 8.60 (1H, d, J=8.0 Hz), 8.67 (2H,s), 8.88 (11H, d, J=7.5 Hz).

MASS (m/z): 1302.4 (M⁺+1).

EXAMPLE 196

IR (KBr): 3353, 2937, 1664, 1627, 1529, 1446, 1255, 1180, 1114, 1087,1064, 1006 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.2-1.6 (8H, m), 1.6-2.7 (15H, m), 2.7-3.6 (5H, m), 3.21 (3H, s),3.6-4.25 (12H, m), 4.25-4.6 (4H, m), 4.6-5.0 (3H, m), 5.11 (2H, m), 5.35(1H, m), 6.39 (1H, d, J=8.0 Hz), 6.57 (1H, m), 6.61 (1H, d, J=8.0 Hz),7.05 (2H, m), 7.14 (2H, d, J=8.8 Hz), 7.22 (1H, m), 7.44 (1H, d, J=8.9Hz), 7.6-7.8 (2H, m), 7.97 (2H, d, J=8.8 Hz), 8.04 (2H, d, J=8.8 Hz),8.11 (2H, d, J=8.8 Hz), 8.39 (1H, d, J=7.5 Hz), 8.68 (1H, m), 8.90(1H,+d, J=6.9 Hz).

MASS (m/z): 1261.4 (M⁺+1).

EXAMPLE 197

IR (KBr): 3349, 2935, 1658, 1635, 1529, 1446, 1255, 1180, 1114, 1087,1062, 1006 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.13 (3H, d, J=5.7 Hz),1.3-1.6 (8H, m), 1.6-2.6 (15H, m), 2.6-3.6 (8H, m), 3.21 (3H, s),3.6-4.3 (12H, m), 4.40 (2H, m), 4.55 (1H, m), 4.65 (1H, m), 4.8 (3H, m),5.16 (3H, m), 6.39 (1H, d, J=8.0 Hz), 6.57 (1H, m), 6.62 (1H, d, J=8.0Hz), 7.14 (2H, d, J=8.8 Hz), 7.34 (1H, m), 7.51 (1H, d, J=9.2 Hz), 7.68(2H, m), 7.97 (2H, d, J=8.8 Hz), 8.04 (2H, d, J=8.8 Hz), 8.11 (2H, d,J=8.8 Hz), 8.20 (1H, d, J=6.7 Hz), 8.57 (1H, m), 8.68 (2H, m), 8.86 (1H,d, J=7.6 Hz), 9.14 (1H, s), 9.40 (1H, m).

MASS (m/z): 1303.3 (M⁺+1).

EXAMPLE 198

IR (KBr): 3353.6, 1658.5, 1635.3, 1529.3, 1444.4, 1255.4 cm⁻¹.

NMR (DMSO-d₆, δ): 0.98 (3H, d, J=6.8 Hz), 1.08 (3H, d, J=5.6 Hz),1.2-5.6 (68H, m), 6.40 (1H, d, J=8.0 Hz), 6.58 (1H, s), 6.60 (1H, d,J=8.1 Hz), 7.14 (2H, d, J=8.9 Hz), 7.97 (2H, d, J=8.7 Hz), 8.08 (2H, d,J=10.8 Hz), 8.13 (2H, d, J=8.9 Hz), 7.3-9.2 (7H, m).

MASS (m/z): 1330.4 (M⁺−Cl).

EXAMPLE 199

IR (KBr): 3349, 2937, 1658, 1627, 1604, 1529, 1446, 1255, 1201, 1114,1083, 1062, 1006 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.10 (3H, d, J=5.7 Hz),1.1-1.5 (10H, m), 1.6-2.6 (17H, m), 2.6-3.8 (12H, m), 3.8-4.3 (10H, m),4.4 (4H, m), 4.78 (2H, m), 5.3 (1H, m), 6.39 (1H, d, J=8.0 Hz), 6.57(1H, m), 6.60 (1H, d, J=8.0 Hz), 7.20 (2H, d, J=9.0 Hz), 7.45 (1H, m),7.73 (3H, m), 7.86 (2H, d, J=8.8 Hz), 7.97 (4H, s), 8.42 (1H, d, J=6.7Hz), 8.73 (1H, d, J=6.7 Hz), 8.84 (1H, s), 10.35 (1H, m).

MASS (m/z): 1280.4 (M⁺+1).

EXAMPLE 200

IR (KBr): 3349, 2935, 1658, 1627, 1606, 1529, 1446, 1251, 1201, 1114,1085, 1064, 1006 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.7 Hz),1.1-1.7 (7H, m), 1.7-2.7 (15H, m), 2.7-3.8 (15H, m), 3.8-4.3 (12H, m),4.45 (4H, m), 4.75 (2H, m), 5.42 (1H, m), 6.39 (1H, d, J=8.0 Hz), 6.57(1H, m), 6.60 (1H, d, J=8.0 Hz), 7.18 (2H, d, J=9.0 Hz), 7.45 (1H, d,J=8.6 Hz), 7.73 (3H, m), 7.92 (2H, d, J=8.8 Hz), 8.08 (4H, s), 8.41 (1H,d, J=6.7 Hz), 8.89 (1H, d, J=6.7 Hz), 10.6 (1H, m).

MASS (m/z): 1241.5 (M⁺+1).

EXAMPLE 201

IR (KBr): 3347, 2937, 1658, 1635, 1531, 1506, 1444, 1255, 1180, 1114,1085, 1060, 1006 cm⁻¹.

NMR (DMSO-d₆, δ): 0.8-1.0 (6H, m), 1.10 (3H, d, J=5.7 Hz), 1.2-1.6 (5H,m), 1.6-2.7 (11H, m), 2.7-3.1 (4H, m), 3.1-4.3 (12H, m), 4.3-4.6 (5H,m), 4.6-4.9 (4H, m), 4.9-5.4 (5H, m), 6.39 (1H, d, J=8.2 Hz), 6.56 (1H,s), 6.61 (1H, d, J=8.2 Hz), 7.13 (2H, d, J=8.8 Hz), 7.40 (1H, m),7.3-7.5 (2H, m), 7.74 (1H, m), 7.85 (2H, d, J=8.8 Hz), 8.00 (2H, d,J=8.8 Hz), 8.06 (2H, d, J=8.8 Hz), 8.41 (1H, m), 8.69 (2H, m), 8.88 (1H,d, J=7.0 Hz).

MASS (m/z): 1144.3 (M⁺+1).

EXAMPLE 202

IR (KBr): 3322, 2935, 1664, 1627, 1606, 1529, 1446, 1255, 1201, 1114,1085, 1064, 1006 cm⁻¹.

NMR (DMSO-d₆, δ): 0.88 (3H, d, J=7.0 Hz), 0.97 (3H, d, J=6.7 Hz), 1.10(3H, d, J=5.7 Hz), 0.8-1.2 (2H, m), 1.2-1.6 (5H, m), 1.6-2.0 (6H, m),2.0-2.7 (9H, m), 2.7-3.1 (4H, m), 3.1-3.8 (9H, m), 3.8-4.3 (8H, m),4.3-4.6 (4H, m), 4.6-4.9 (3H, m), 4.95 (1H, m), 5.12 (1H, d, J=7.3 Hz),5.3-5.4 (3H, m), 6.39 (1H, d, J=8.0 Hz), 6.57 (1H, s), 6.61 (1H, d,J=8.0 Hz), 7.19 (2H, d, J=8.9 Hz), 7.44 (1H, d, J=9.8 Hz), 7.7 (1H, m),7.93 (2H, d, J=8.8 Hz), 8.08 (4H, s), 8.41 (1H, m), 8.70 (2H, s), 8.91(1H, d, J=6.6 Hz), 10.10 (1H, m).

MASS (m/z): 1255.4 (M⁺+1).

EXAMPLE 203

IR (KBr): 3344, 2940, 1658, 1627, 1531, 1496, 1246, 1180, 1114, 1083,1062, 1004 cm⁻¹.

NMR (DMSO-d₆, δ): 0.97 (3H, d, J=6.7 Hz), 1.09 (3H, d, J=5.7 Hz),1.1-1.5 (8H, m), 1.65 (2H, m), 1.7-2.0 (6H, m), 2.1-2.7 (7H, m), 2.8-3.1(4H, m), 3.1-3.8 (9H, m), 3.97 (7H, m), 4.16 (2H, d, J=6.5), 4.23 (1H,m), 4.4 (5H, m), 4.75 (3H, m), 4.98 (1H, m), 5.27 (1H, m), 6.39 (1H, d,J=8.0 Hz), 6.57 (1H, m), 6.61 (1H, d, J=8.0 Hz), 7.12 (2H, d, J=8.8 Hz),7.44 (1H, d, J=8.8 Hz), 7.68 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.8 Hz),7.6-7.9 (3H, m), 7.96 (2H, d, J=8.8 Hz), 8.42 (1H, m), 8.74 (1H, d,J=6.8 Hz), 10.06 (1H, m).

MASS (m/z): 1157.6 (M⁺+1).

EXAMPLE 204

IR (KBr): 3320, 2933, 1658, 1629, 1610, 1510, 1446, 1255, 1234, 1114,1087, 1064, 1006 cm⁻¹.

NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6.7 Hz), 1.06 (3H, d, J=5.7 Hz),1.2-1.5 (11H, m), 1.5-1.8 (3H, m), 1.8-2.1 (5H, m), 2.1-2.7 (6H, m),2.8-3.1 (4H, m), 3.1-3.8 (13H, m), 3.21 (3H, s), 3.8-4.1 (7H, m), 3.90(2H, d, J=6.4 Hz), 3.95 (1H, m), 4.2-4.5 (5H, m), 4.75 (3H, m), 5.24(1H, m), 6.39 (1H, d, J=8.0 Hz), 6.57 (1H, m), 6.60 (1H, d, J=8.0 Hz),6.91 (2H, d, J=8.8 Hz), 7.03 (2H, d, J=8.8 Hz), 7.17 (1H, m), 7.42 (1H,d, J=8.4 Hz), 7.72 (5H, m), 7.83 (2H, d, J=8.4 Hz), 8.43 (1H, m), 8.50(1H, d, J=6.7 Hz).

MASS (m/z): 1233.4 (M⁺+1).

EXAMPLE 205

IR (KBr): 1651, 1539, 1514, 1234 cm⁻¹.

NMR (DMSO-d₆, δ): 0.85 (9H, s), 0.8-1.3 (11H, m), 1.3-2.4 (13H, m),2.4-5.4 (40H, m), 6.39 (1H, d, J=7.5 Hz), 6.5-6.7 (2H, m), 7.04 (2H, d,J=8.6 Hz), 7.3-8.0 (5H, m), 8.3-8.9 (3H, m), 9.9-10.1 (1H, m).

MASS (m/z): 1137 (M⁺+1).

Elemental Analysis Calcd. for C₅₆H₈₄N₁₀O₁₅.3HCl.8H₂O: C, 48.36, H, 7.46,N, 10.07. Found: C, 48.25, H, 7.20, N, 9.81.

EXAMPLE 206

IR (KBr): 1699, 1678, 1651, 1539, 1514, 1456 cm⁻¹.

MASS (m/z): 1264 (M⁺+1).

1. A polypeptide compound of the following general formula (I):

wherein R¹ is hydrogen or acyl group, R² and R³ are independentlyhydrogen; lower alkyl which may have one or more suitable substituent(s)selected from the group consisting of amino, carboxy, sulfinic acidgroup, sulfonic acid group, hydroxy(lower)alkylamino which may havehydroxy(lower)alkyl, hydroxysulfonyloxy, imino, lower alkoxy, oxo, loweralkylthio, cyano(lower)alkylidene, and heterocyclic group which may haveone or more lower alkyl; lower alkoxycarbonyl which may have one or moresuitable substituent(s) selected from the group consisting of loweralkanoyloxy and heterocyclic group; lower alkenyloxycarbonyl;ar(lower)alkoxycarbonyl; lower alkanoyl which may have one or moresuitable substituent(s) selected from the group consisting of amino,hydroxy and heterocyclic group; heterocycliccarbonyl; mono ordi(lower)alkylcarbamoyl; sulfonic acid group; heterocyclic group whichmay have one or more suitable substituent(s) selected from the groupconsisting of lower alkyl, hydroxy(lower)alkyl, carboxy(lower)alkanoylwhich may have amino, heterocycliccarbonyl, cyclo(lower)alkyl, and oxo;lower alkylidene which may have mono or di lower alkylamino;carboxy(higher)alkyl or cyano, R⁴ is hydrogen or hydroxy, R⁵ ishydrogen, hydroxy, lower alkoxy or hydroxysulfonyloxy, and R⁶ is hydroxyor acyloxy, or a salt thereof.
 2. A compound of claim 1, wherein R² andR³ are independently hydrogen, methyl, aminoethyl, aminobutyl,aminopentyl, carboxymethyl, carboxyethyl, carboxypentyl, sulfonylmethyl,hydroxysulfonylpropyl, hydroxysulfonylbutyl,dihydroxyisopropylaminobutyl, hydroxysulfonyloxypropyl,1-iminomethoxypropyl, 1-iminocarbamoylethyl, amidino,2-cyano-1-methylthiovinyl, 2-cyano-1-aminovinyl, methylpyrazolylmethyl,tert-butoxycarbonyl, acetyloxymethoxycarbonyl,1,3-dioxa-2-oxo-4-methylcyclopentenylmethoxycarbonyl, allyloxycarbonyl,fluorenylmethoxycarbonyl, acetyl, aminopropionyl, aminovaleryl,diaminohexanoyl, 2-hydroxy4-aminovaleryl, 2-amino-3-pyrazolylpropionyl,pyrrolidinylcarbonyl, morpholinocarbonyl, dimethylcarbamoyl,diethylcarbamoyl, hydroxysulfonyl, piperidyl, dimethylpiperidyl,hydroxyethylmethylpiperidyl, carboxypropionylpiperidyl,4-amino-4-carboxybutyrylpiperidyl, azetidinylcarbonylpiperidyl,dimethyl-1,3-dioxacyclohexyl, cyclohexyl-1,3-dioxacyclohexyl,dioxothiopyranyl, dimethylaminomethylidene, carboxyheptyl or cyano.
 3. Acompound of claim 1, wherein R¹ is hydrogen; lower alkoxycarbonyl; aroylwhich has heterocyclic group substituted with aryl having a suitablesubstituent selected from the group consisting of lower alkoxy, loweralkoxy(lower)alkoxy, lower alkoxy(higher)alkoxy, aryl substituted withlower alkoxy(lower)alkoxy, cyclo(lower)alkyl, cyclo(lower)alkyloxy, arylsubstituted with lower alkoxy, aryl substituted with loweralkoxy(lower)alkyl, aryl substituted with heterocyclic group,heterocyclic group substituted with cyclo(lower)alkyl, heterocyclicgroup, heterocyclic group substituted with aryl, heterocyclic groupsubstituted with aryloxy, heterocyclic group substituted withar(lower)alkoxy, heterocyclic group substituted with lower alkoxy andaryl, higher alkoxy, heterocyclic(higher)alkoxy, loweralkoxy(higher)alkylsulfonyl, aryloxy(lower)alkoxy, heterocyclic groupsubstituted with cyclo(lower)alkyloxy, heterocyclic group substitutedwith aryl having lower alkoxy(lower)alkoxy, heterocyclic groupsubstituted with lower alkylthio, heterocyclic group substituted withlower alkoxy(lower)alkylthio, and heterocyclic group substituted withlower alkoxy(lower)alkoxy; aroyl which has aryl substituted with asuitable substituent selected from the group consisting of lower alkoxyhaving cyclo(lower)alkyl and amino, lower alkoxy havingcyclo(lower)alkyl and protected amino, aryl having lower alkoxy,heterocyclic group having lower alkyl, heterocyclic group havingcyclo(lower)alkyl, and heterocyclic group having aryl substituted withheterocyclic group; aroyl which has heterocyclic group substituted withcyclo(lower)alkyl having one or more suitable substituent(s) selectedfrom the group consisting of lower alkyl, lower alkoxy,cyclo(lower)alkyl, and cyclo(lower)alkyl substituted with lower alkoxy;higher alkanoyl; aroyl which has higher alkoxy; or heterocycliccarbonylwhich has a suitable substituent(s) selected from the group consistingof heterocyclic group substituted with higher alkyl, heterocyclic groupsubstituted with aryl having lower alkoxy, heterocyclic groupsubstituted with aryl having heterocyclic group, and aryl substitutedwith lower alkoxy(higher)alkoxy.
 4. A compound of claim 3, wherein R¹ ishydrogen; (C₁-C₄)alkoxycarbonyl; benzoyl which has thiazolyl substitutedwith phenyl having (C₄-C₆)alkoxy; benzoyl which has thiadiazolylsubstituted with phenyl having a suitable substituent selected from thegroup consisting of (C₁-C₄)alkoxy(C₄-C₆)alkoxy, phenyl substituted with(C₁-C₄)alkoxy(C₁-C₄)alkoxy, (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy,cyclo(C₄-C₆)alkyl, cyclo(C₄-C₆)alkyloxy, phenyl substituted with(C₁-C₄)alkoxy, phenyl substituted with (C₁-C₄)alkoxy(C₁-C₄)alkyl, phenylsubstituted with di(C₁-C₄)alkylmorpholino, piperazinyl substituted withcyclo(C₄-C₆)alkyl, piperazinyl substituted with cyclo(C₄-C₆)alkyl having(C₁-C₄)alkyl; piperidyl, piperidyl substituted with phenyl, piperidylsubstituted with phenoxy, piperidyl substituted with benzyloxy,piperidyl substituted with (C₁-C₄)alkoxy and chlorophenyl, and phenylhaving di(C₁-C₄)alkylmorpholino; benzoyl which has pyrimidinylsubstituted with phenyl having (C₇-C₁₄)alkoxy; benzoyl which hasisoxazolyl substituted with phenyl having a suitable substituentselected from the group consisting of (C₄-C₆)alkoxy,(C₁-C₄)alkoxy(C₄-C₆)alkoxy, (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy, (C₇-C₁₄)alkoxysubstituted with di(C₁-C₄)alkylmorpholino, and di(C₁-C₄)alkylmorpholino;benzoyl which has oxadiazolyl substituted with phenyl having a suitablesubstituent selected from the group consisting of (C₄-C₆)alkoxy,(C₁-C₄)alkoxy(C₇-C₁₄)alkoxy, (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy, and(C₁-C₄)alkoxy(C₇-C₄)alkylsulfonyl; benzoyl which has piperazinylsubstituted with phenyl having a suitable substituent selected from thegroup consisting of (C₁-C₄)alkoxy(C₄-C₆)alkoxy,(C₁-C₄)alkoxy(C₇-C₁₄)alkoxy, phenoxy(C₁-C₄)alkoxy, cyclo(C₄-C₆)alkyl,phenyl substituted with (C₁-C₄)alkoxy(C₄-C₆)alkoxyphenyl, phenylsubstituted with di(C₁-C₄)alkylmorpholino, piperidyl substituted withcyclo(C₄-C₆)alkyloxy, piperidyl substituted with phenyl, piperidylsubstituted with (C₁-C₄)alkoxy(C₁-C₄)alkoxyphenyl, piperidyl substitutedwith (C₁-C₄)alkylthio, piperidyl substituted with(C₁-C₄)alkoxy(C₄-C₆)alkylthio, piperidyl substituted withcyclo(C₄-C₆)alkanespiro, piperidyl substituted withdioxacyclo(C₄-C₆)alkanespiro, piperidyl substituted with (C₁-C₄)alkoxyand phenyl, piperidyl substituted with (C₁-C₄)alkoxy and chlorophenyl,and di(C₁-C₄)alkylmorpholino; benzoyl which has piperazinyl substitutedwith cyclo(C₄-C₆)alkyl having a suitable substituent selected from thegroup consisting of cyclo(C₄-C₆)alkyl, (C₄-C₆)alkyl, cyclo(C₄-C₆)alkyland (C₁-C₄)alkoxy, and cyclo(C₄-C₆)alkyl substituted with (C₁-C₄)alkoxy;benzoyl which has imidazothiadiazolyl substituted with phenyl having asuitable substituent selected from the group consisting of(C₄-C₆)alkoxy, (C₁-C₄)alkoxy(C₄-C₆)alkoxy, cyclo(C₄-C₆)alkyloxy,piperazinyl substituted with cyclo(C₄-C₆)alkyl, piperidyl substitutedwith (C₁-C₄)alkoxy(C₁-C₄)alkoxy, piperidyl substituted with(C₁-C₄)alkoxy(C₄-C₆)alkoxy, piperidyl substituted with(C₁-C₄)alkoxy(C₄-C₆)alkylthio, and di(C₁-C₄)alkylmorpholino; benzoylwhich has phenyl substituted with a suitable substituent selected fromthe group consisting of (C₁-C₄)alkoxy having cyclo(C₄-C₆)alkyl and(C₁-C₄)alkoxycarbonylamino, (C₁-C₄)alkoxy having cyclo(C₄-C₆)alkyl andamino, phenyl having (C₄-C₆)alkoxy, thiazolyl having (C₄-C₆)alkyl,piperazinyl having cyclo(C₄-C₆)alkyl, piperazinyl having phenylsubstituted with di(C₁-C₄)alkylmorpholino, and benzoxazolyl having(C₄-C₆)alkyl; benzoyl which has (C₇-C₁₄)alkoxy; thiadiazolylcarbonylwhich has pyrazolyl substituted with a suitable substituent selectedfrom the group consisting of (C₇-C₁₄)alkyl, phenyl having (C₄-C₆)alkoxy,and phenyl having piperidyl; piperazinylcarbonyl which has xylylsubstituted with (C₁-C₄)alkoxy(C₇-C₁₄)alkoxy; or (C₇-C₁₄)alkanoyl.
 5. Acompound of claim 4, wherein R¹ is hydrogen; benzoyl which has thiazolylsubstituted with phenyl having pentyloxy; benzoyl which has thiadiazolylsubstituted with phenyl having a suitable substituent selected from thegroup consisting of methoxyhexyloxy, methoxyoctyloxy, phenyl substitutedwith methoxyethoxy, phenyl substituted with methoxybutoxy,methoxyheptyloxy, cyclohexyl, cyclohexyloxy, phenyl substituted withpropoxy, phenyl substituted with ethoxymethyl, phenyl substituted withmethoxypropoxy, phenyl substituted with dimethylmorpholino, piperazinylsubstituted with cyclohexyl, piperazinyl substitued withmethylcyclohexyl, piperidyl, piperidyl substituted with phenyl piperidylsubstituted with phenoxy, piperidyl substituted with benzyloxy,piperidyl substituted with methoxy and chlorophenyl, anddimethylmorpholino; benzoyl which has pyrimidinyl substituted withphenyl having octyloxy; benzoyl which has isoxazolyl substituted withphenyl having a suitable substituent selected from the group consistingof pentyloxy, methoxyhexyloxy, phenyl having methoxyheptyloxy, heptyloxysubstituted with dimethylmorpholino, octyloxy substituted withdimethylmorpholino, and dimethylmorpholino; benzoyl which hasoxadiazolyl substituted with phenyl having a suitable substituentselected from the group consisting of pentyloxy, methoxyheptyloxy,methoxynonyloxy, methoxyheptylsulfonyl, and methoxynonylsulfonyl;benzoyl which has piperazinyl substituted with phenyl having a suitablesubstituent selected from the group consisting of methoxyhexyloxy,methoxyheptyloxy, phenoxypropoxy, cyclohexyl, phenyl substituted withmethoxypentyloxyphenyl, phenyl substituted with dimethylmorpholino,piperidyl substituted with cyclohexyloxy, piperidyl substituted withphenyl, piperidyl substituted with methoxybutoxyphenyl, piperidylsubstituted with propylthio, piperidyl substituted withmethoxyhexylthio, piperidyl substituted with cyclobutanespiro, piperidylsubstituted with dioxacyclobutanespiro, piperidyl substituted withmethoxy and phenyl, piperidyl substituted with methoxy and chlorophenyl,and dimethylmorpholino; benzoyl which has piperazinyl substituted withcyclohexyl having a suitable substituent selected from the groupconsisting of tert-butyl, cyclohexyl and methoxy, and cyclohexylsubstituted with propoxy; benzoyl which has imidazothiadiazolylsubstituted with phenyl having a suitable substituent selected from thegroup consisting of methoxybutoxy, cyclohexyloxy, piperazinylsubstituted with cyclohexyl, piperidyl substitued with methoxypropoxy,piperidyl substituted with methoxybutoxy, piperidyl substituted withmethoxypentyloxy, piperidyl substituted with methoxyhexyloxy, piperidylsubstituted with methoxyhexylthio, and dimethylmorpholino; benzoyl whichhas phenyl substituted with a suitable substituent selected from thegroup consisting of propoxy having cyclohexyl andtert-butoxycarbonylamino, cyclohexyl and amino, phenyl having pentyloxy,thiazolyl having pentyl, piperazinyl having cyclohexyl, piperazinylhaving phenyl substituted with dimethylmorpholino, and benzoxazolylhaving pentyl; benzoyl which has octyloxy; thiadiazolylcarbonyl whichhas pyrazolyl substituted with a suitable substituent selected from thegroup consisting of decyl, phenyl having hexyloxy, and phenyl havingpiperidyl; piperazinylcarbonyl which has xylyl substituted withmethoxyheptyloxy; or palmitoyl.
 6. A process for preparing a polypeptidecompound (I) of claim 1, or a salt thereof, which comprises, i) reducinga compound (II) of the formula:

 or a salt thereof, to give a compound (Ia) of the formula:

 or a salt thereof, or ii) subjecting a compound (Ia) of the formula:

 or a salt thereof, to protective reaction of amino, to give a compound(Ib) of the formula:

wherein R_(a) ² is hydrogen, lower alkyl which may have one or moresuitable substituent(s) selected from the group consisting of amino,carboxy, sulfinic acid group, sulfonic acid group,hydroxy(lower)alkylamino which may have hydroxy(lower)alkyl,hydroxysulfonyloxy, imino, lower alkoxy, oxo, lower alkylthio,cyano(lower)alkylidene, and heterocyclic group which may have one ormore lower alkyl; lower alkoxycarbonyl which may, have one or moresuitable substituent(s) selected from the group consisting of loweralkanoyloxy and heterocyclic group; lower alkenyloxycarbonyl;ar(lower)alkoxycarbonyl; lower alkanoyl which may have one or moresuitable substituent(s) selected from the group consisting of amino,hydroxy and heterocyclic group; heterocycliccarbonyl; mono ordi(lower)alkylcarbamoyl; sulfonic acid group; heterocyclic group whichmay have one or more suitable substituent(s) selected from the groupconsisting of lower alkyl, hydroxy(lower)alkyl, carboxy(lower)alkanoylwhich may have amino, heterocycliccarbonyl, cyclo(lower)alkyl, and oxo;lower alkylidene which may have mono or di lower alkylamino;carboxy(higher)alkyl or cyano, and R_(a) ³ is lower alkyl which may haveone or more suitable substituent(s) selected from the group consistingof amino, carboxy, sulfinic acid group, sulfonic acid group,hydroxy(lower)alkylamino which may have hydroxy(lower)alkyl,hydroxysulfonyloxy, imino, lower alkoxy oxo, lower alkylthio,cyano(lower)alkylidene, and heterocyclic group which may have one ormore lower alkyl; lower alkoxycarbonyl which may have one or moresuitable substituent(s) selected from the group consisting of loweralkanoyloxy and heterocyclic group; lower alkenyloxycarbonyl;ar(lower)alkoxycarbonyl; lower alkanoyl which may have one or moresuitable substituent(s) selected from the group consisting of amino,hydroxy and heterocyclic group; heterocycliccarbonyl; mono ordi(lower)alkylcarbamoyl; sulfonic acid group; heterocyclic group whichmay have one or more suitable substituent(s) selected from the groupconsisting of lower alkyl, hydroxy(lower)alkyl, carboxy(lower)alkanoylwhich may have amino, heterocycliccarbonyl, cyclo(lower)alkyl, and oxo;lower alkylidene which may have mono or di lower alkylamino;carboxy(higher)alkyl or cyano, or a salt thereof, or iii) subjecting acompound (Ic) of the formula:

wherein R_(a) ⁵ is hydroxysulfonyloxy, or a its reactive derivative atthe sulfonic acid group, or a salt thereof, to hydrolysis reaction ofthe sulfonic acid group, to give a compound (Id) of the formula:

wherein R_(b) ⁵ is hydroxy, or a salt thereof, or iv) subjecting acompound (Ie) of the formula:

wherein R_(b) ³ is amino protective group, or a salt thereof, toelimination reaction of amino protective group, to give a compound (If)of the formula:

 or a salt thereof, or v) reducing a compound (II) of the formula:

 or its reactive derivative or a salt thereof, and then reacting with acompound (IV) of the formula:R_(c) ³—OH  (IV) wherein R_(c) ³ is lower alkoxycarbonyl which may haveone or more suitable substituent(s) selected from the group consistingof lower alkanoyloxy and heterocyclic group; lower alkenyloxycarbonyl;ar(lower)alkoxycarbonyl; lower alkanoyl which may have one or moresuitable substituent(s) selected from the group consisting of amino,hydroxy and heterocyclic group; heterocycliccarbonyl; mono ordi(lower)alkylcarbamoyl; sulfonic acid group, or its reactive derivativeor a salt thereof, to give a compound (Ig) of the formula:

 or a salt thereof, or vi) reacting a compound (Ih) of the formula:

 or its reactive derivative or a salt thereof, with a compound (V) ofthe formula:R_(b) ²—OH  (V) wherein R_(b) ² is lower alkoxycarbonyl which may haveone or more suitable substituent(s) selected from the group consistingof lower alkanoyloxy and heterocyclic group; lower alkenyloxycarbonyl;ar(lower)alkoxycarbonyl; lower alkanoyl which may have one or moresuitable substituent(s) selected from the group consisting of amino,hydroxy and heterocyclic group; heterocycliccarbonyl; mono ordi(lower)alkylcarbamoyl; sulfonic acid group, or its reactive derivativeor a salt thereof, to give a compound (Ii) of the formula:

 or a salt thereof, or vii) reacting a compound (Ij) of the formula:

 or its reactive derivative at the amino group, or a salt thereof, witha compound (III) of the formula:R_(a) ¹—OH  (III) wherein R_(a) ¹ is acyl group, or its reactivederivative at the carboxy group, or a salt thereof, to give a compound(Ik) of the formula:


7. A composition which comprises, as an active ingredient, a compound ofclaim 1 or a pharmaceutically acceptable salt thereof in admixture withpharmaceutically acceptable carrier or excipients.
 8. A method oftreating an infectious diseases caused by a fungus comprisingadministering to a human being or an animal subject in need thereof acompound according to claim 1 for a time and under conditions to treatsaid disease.